Novel pyrimidines as egfr inhibitors and methods of treating disorders

ABSTRACT

The application relates to a compound having Formula (I′): 
     
       
         
         
             
             
         
       
     
     which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.

RELATED APPLICATION

This application claims the benefit of, and priority to, U.S.provisional application No. 62/194,594, filed Jul. 20, 2015, the entirecontents of which are incorporated herein by reference.

GOVERNMENT SUPPORT

This invention was made with government support under grant number P01CA154303 awarded by The National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND

The epidermal growth factor receptor (EGFR, Erb-B1) belongs to a familyof proteins, involved in the proliferation of normal and malignant cells(Artega, C. L., J. Clin. Oncol. 19, 2001, 32-40). Overexpression of EGFRis present in at least 70% of human cancers (Seymour, L. K., Curr. DrugTargets 2, 2001, 117-133), such as non-small cell lung carcinomas(NSCLC), breast cancers, gliomas, squamous cell carcinoma of the headand neck, and prostate cancer (Raymond et al., Drugs 60 Suppl. 1, 2000,discussion 41-2; Salomon et al., Crit. Rev. Oneal. Hematol. 19, 1995,183-232; Voldborg et al., Ann. Oneal. 8, 1997, 1197-1206). The EGFR-TKis therefore widely recognized as an attractive target for the designand development of compounds that can specifically bind and inhibit thetyrosine kinase activity and its signal transduction pathway in cancercells, and thus can serve as either diagnostic or therapeutic agents.For example, the EGFR tyrosine kinase (EGFR-TK) reversible inhibitor,TARCEVA®, is approved by the FDA for treatment of NSCLC and advancedpancreatic cancer. Other anti-EGFR targeted molecules have also beenapproved including AFATINIB® and IRESSA®.

EGFR tyrosine kinase inhibitors (TKIs) are effective clinical therapiesfor EGFR mutant advanced NSCLC patients (Mok, T. S., et al., N. Engl. J.Med. 361, 2009, 947-57; Paez, J. G., et al., Science. 304, 2004,1497-500; Lynch, T. J., et al., N. Engl. J. Med. 350, 2004, 2129-39;Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46). Several randomizedclinical trials have demonstrated that EGFR TKIs are more effective, asmeasured by response rate (RR) and progression free survival (PFS), thanchemotherapy when used as initial systemic treatment for advanced EGFRmutant NSCLC (Mok, T. S., et al., N. Engl. J. Med. 361, 2009, 947-57;Rosell, R., et al., Lancet Oncol. 13, 2012, 239-46; Sequist, L. V. etal., J. Clin. Oncol. 31, 2013, 3327-34; Wu, Y. L., et al., Lancet Oncol.15, 2014, 213-22; Maemondo, M., et al. N. Engl. J. Med. 362, 2010,2380-8; Zhou, C., et al., Lancet Oncol. 12, 2011, 735-42; Mitsudomi, T.,et al., Lancet Oncol. 11, 2010, 121-8). However, the vast majority ofpatients will develop disease progression following successful treatmentwith an EGFR TKI. The most common mechanism of resistance is mutation ofthe EGFR ATP-binding site in a manner that renders the site lesssensitive to drug inhibition.

Certain EGFR mutations (i.e., G719X, exon 19 deletions/insertions,L858R, and L861Q) predict favorable responses to EGFR tyrosine kinaseinhibitors (TKIs) in advanced NSCLC and other cancers. However, EGFRexon 20 insertion mutations (˜10% of all EGFR mutations) are generallyassociated with insensitivity to available TKIs (gefitinib, erlotinib,and afatinib) and the basis of this primary resistance is poorlyunderstood.

Currently, no approved EGFR inhibitors are available for treating Exon20 mutant EGFR cancers. For these reasons, there remains a considerableneed for novel and potent small molecule EGFR modulators.

SUMMARY

The present application relates to compounds of Formula (I′), as definedherein, that are capable of modulating EGFR activity. The applicationfeatures methods of treating or preventing a disease in which EGFR playsa role in a subject in need thereof by administering to the subject atherapeutically effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, as defined herein. The methods of theapplication can be used to treat diseases in which EGFR plays a role byinhibiting the kinase activity of EGFR.

A first aspect of the application relates to compounds of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein R₁, R₂, R₃, R₄, and R₅ aredescribed herein in detail below.

Another aspect of the present application relates to a pharmaceuticalcomposition comprising a compound of Formula (I′), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, and a pharmaceutically acceptable carrier.

Another aspect of the present application relates to a method ofinhibiting a kinase. The method comprises administering to a subject inneed thereof an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

In another aspect, the present application relates to a method ofinhibiting epidermal growth factor receptor (EGFR). The method comprisesadministering to a subject in need thereof an effective amount of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present application relates to a method oftreating or preventing a disease. The method comprises administering toa subject in need thereof an effective amount of a compound of Formula(I′), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

In another aspect, the present application relates to a method oftreating or preventing a kinase mediated disorder. The method comprisesadministering to a subject in need thereof an effective amount of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present application relates to a method oftreating or preventing a disease, wherein the disease is resistant to anEGFR targeted therapy, such as a therapy with gefitinib or erlotinib.The method comprises administering to a subject in need thereof aneffective amount of a compound of Formula (I′), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the present application relates to a method oftreating or preventing cancer, wherein the cancer cell comprises anactivated EGFR. The method comprises administering to a subject in needthereof an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the present application relates to a method oftreating or preventing cancer in a subject, wherein the subject isidentified as being in need of EGFR inhibition for the treatment orprevention of cancer. The method comprises administering to the subjectan effective amount of a compound of Formula (I′), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the present application relates to a method oftreating or preventing cancer, wherein the cancer cell comprises anactivated ERBB2. The method comprises administering to a subject in needthereof an effective amount of a compound of Formula (I′), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the present application relates to a method oftreating or preventing cancer in a subject, wherein the subject isidentified as being in need of ERBB2 inhibition for the treatment ofcancer. The method comprises administering to the subject an effectiveamount of a compound of Formula (I′), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the present application relates to a kit comprising acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the present application relates to a compound ofFormula (I′), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in the manufactureof a medicament for treating or preventing a disease in which EGFR playsa role.

Another aspect of the present application relates to the use of acompound of Formula (I′), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in thetreatment or prevention of a disease in which EGFR plays a role.

The present application provides inhibitors of EGFR, such as EGFRcontaining one or more mutations, that are therapeutic agents in thetreatment or prevention of diseases such as cancer and metastasis.

The present application further provides compounds and compositions withan improved efficacy and/or safety profile relative to known EGFRinhibitors. The present application also provides agents with novelmechanisms of action toward EGFR kinases in the treatment of varioustypes of diseases including cancer and metastasis.

The details of the application are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the applicationwill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this application belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a Western blot showing the levels of pEGFR, EGFR, and tubulinin cells having wild type EGFR or mutant EGFR after treatment withCompound I-1, dacomitinib, WZ4002, or AZD9291 for 24 hours.

FIG. 1B is a Western blot showing the levels of pEGFR, EGFR, and tubulinin cells having mutant EGFR after treatment with Compound I-1,dacomitinib, WZ4002, or AZD9291 for 24 hours.

FIG. 2A is a western blot showing the levels of pEGFR, EGFR, and tubulinin cells having wild type EGFR or mutant EGFR after treatment withCompound I-5 or dacomitinib for 24 hours.

FIG. 2B is a western blot showing the levels of pEGFR, EGFR, and tubulinin cells having mutant EGFR after treatment with Compound I-5 anddacomitinib for 24 hours.

FIG. 3A is a graph showing percent inhibition of cell growth at 72 hoursin two cells lines harboring mutant EGFR kinases, DFCI158-229 andDFCI127c, whose growth is dependent on mutant EGFR kinase activity,relative to untreated cells, when treated with various concentrations ofgefitinib and dacomitinib.

FIG. 3B is a graph showing percent inhibition of cell growth at 72 hoursin two cells lines harboring mutant EGFR kinases, DFCI158-229 andDFCI127c, whose growth is dependent on mutant EGFR kinase activity,relative to untreated cells, when treated with various concentrations ofgefitinib and dacomitinib.

FIG. 4A is a graph showing percent inhibition of cell growth at 72 hoursin two cells lines harboring mutant EGFR kinases, DFCI158-229 andDFCI127c, whose growth is dependent on mutant EGFR kinase activity,relative to untreated cells, when treated with various concentrations ofCompound I-1.

FIG. 4B is a graph showing percent inhibition of cell growth at 72 hoursin two cells lines harboring mutant EGFR kinases, DFCI158-229 andDFCI127c, whose growth is dependent on mutant EGFR kinase activity,relative to untreated cells, when treated with various concentrations ofCompound I-4.

DETAILED DESCRIPTION Compounds of the Application

A first aspect of the application relates to compounds of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein:

R₁ is phenyl or heteroaryl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, wherein the phenyl orheteroaryl is optionally substituted with one or more R₈;

each R₈ is independently halogen, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, OH, NH₂, NH(C₁-C₃) alkyl, orN((C₁-C₃) alkyl)₂;

R₂ is H or (C₁-C₃) alkyl;

R₃ is

R₆ is (C₂-C₄) alkenyl optionally substituted with one or more R₉;

each R₉ is independently NH₂, NH(C₁-C₃) alkyl, N((C₁-C₃) alkyl)₂, orheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more substituents independently selected fromhalogen, OH, and C(O)(C₁-C₃) alkyl;

R₇ is H or (C₁-C₃) alkyl;

R₄ is

R₁₀ is (C₁-C₃) alkyl optionally substituted with C(O)NH—(C₁-C₃) alkyl,C(O)N((C₁-C₃) alkyl)₂, or a heterocyclyl comprising a 5- or 6-memberedring and 1-3 heteroatoms selected from N, O, and S, or R₁₀ isheterocyclyl comprising a 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S optionally substituted with one or more(C₁-C₃) alkyl;

each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, or halogen;

n is 0, 1, or 2; and

R₅ is H or (C₁-C₃) alkyl;

provided that when R₂, R₅ and R₇ are each H, R₆ is ethenyl, and R₄ is

then R₁ is not unsubstituted phenyl.

(1a) In some embodiments of Formula (I′), R₁ is phenyl optionallysubstituted with one or more R₈. In other embodiments, R₁ is phenyloptionally substituted with one to three R₈. In other embodiments, R₁ isphenyl substituted with at least one R₈, wherein the at least one R₈ isat the ortho position. In other embodiments, R₁ is phenyl substitutedwith at least one R₈, wherein the at least one R₈ is at the metaposition. In other embodiments, R₁ is phenyl substituted with at leastone R₈, wherein the at least one R₈ is at the para position. In otherembodiments, R₁ is phenyl.

(1b) In some embodiments of Formula (I′), R₁ is heteroaryl comprisingone or two 5- or 6-membered rings and 1-4 heteroatoms selected from N,O, and S, optionally substituted with one or more R₈. In otherembodiments, R₁ is heteroaryl comprising one 5- or 6-membered ring and1-4 heteroatoms selected from N, O, and S, optionally substituted withone or more R₈. In other embodiments, R₁ is heteroaryl comprising two 5-or 6-membered rings and 1-4 heteroatoms selected from N, O, and S,optionally substituted with one or more R₈. In other embodiments, R₁ ispyridinyl or benzothiophenyl optionally substituted with one or more R₈.In other embodiments, R₁ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, orbenzothiophenyl optionally substituted with one or more R₈. In otherembodiments, R₁ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,

optionally substituted with one to three R₈. In further embodiments, R₁is 2-pyridinyl, 3-pyridinyl,

optionally substituted with one to three R₈.

(2a) In some embodiments of Formula (I′), at least one R₈ is halogen(e.g., F, Cl, Br, or I). In some embodiments, at least one R₈ is F orCl.

(2b) In some embodiments of Formula (I′), at least one R₈ is (C₁-C₃)alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

(2c) In some embodiments of Formula (I′), at least one R₈ is (C₁-C₃)haloalkyl (e.g., CH₂F, CHF₂, or CF₃).

(2d) In some embodiments of Formula (I′), at least one R₈ is OH, NH₂,NH(C₁-C₃) alkyl, or N((C₁-C₃) alkyl)₂. In other embodiments, at leastone R₈ is OH or NH₂. In other embodiments, at least one R₈ is NH(C₁-C₃)alkyl (e.g., methylamino, ethylamino, propylamino, or i-propylamino) orN((C₁-C₃) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordii-propylamino).

(3a) In some embodiments of Formula (I′), R₂ is H.

(3b) In some embodiments of Formula (I′), R₂ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂ is methylor ethyl. In further embodiments, R₂ is methyl. In further embodiments,R₂ is in the S-configuration or R-configuration. In further embodiments,R₂ is in the S-methyl or R-methyl.

(4) In some embodiments of Formula (I′), R₃ is

(5a) In some embodiments of Formula (I′), R₆ is (C₂-C₄) alkenyl (e.g.,ethenyl, propenyl, or butenyl). In other embodiments, R₆ is ethenyl orpropenyl. In further embodiments, R₆ is ethenyl.

(5b) In some embodiments of Formula (I′), R₆ is (C₂-C₄) alkenyl (e.g.,ethenyl, propenyl, or butenyl) substituted with one or more R₉. In otherembodiments, R₆ is ethenyl or propenyl substituted with one or more R₉.In further embodiments, R₆ is

(6a) In some embodiments of Formula (I′), at least one R₉ is NH₂,NH(C₁-C₃) alkyl, or N((C₁-C₃) alkyl)₂. In other embodiments, at leastone R₉ is NH₂. In other embodiments, at least one R₉ is NH(C₁-C₃) alkyl(e.g., methylamino, ethylamino, propylamino, or i-propylamino) orN((C₁-C₃) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordii-propylamino). In other embodiments, at least one R₉ is methylamino,ethylamino, dimethylamino, or diethylamino. In other embodiments, atleast one R₉ is dimethylamino or diethylamino. In further embodiments,at least one R₉ is dimethylamino.

(6b) In some embodiments of Formula (I′), at least one R₉ isheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more substituents independently selected fromhalogen (e.g., F, Cl, Br, or I), OH, and C(O)(C₁-C₃) alkyl (e.g.,C(O)CH₃, C(O)CH₂CH₃, C(O)CH₂CH₂CH₃, or C(O)CH(CH₃)₂). In otherembodiments, at least one R₉ is heterocyclyl comprising a 5- to7-membered ring and 1-3 heteroatoms selected from N, O, and S, whereinthe heterocyclyl is optionally substituted with one to two substituentsindependently selected from halogen, OH, and C(O)(C₁-C₃) alkyl. In otherembodiments, at least one R₉ is heterocyclyl comprising a 6- or7-membered ring and 1-3 heteroatoms selected from N, O, and S, whereinthe heterocyclyl is optionally substituted with one or more substituentsindependently selected from halogen, OH, and C(O)(C₁-C₃) alkyl. In otherembodiments, at least one R₉ is heterocyclyl comprising a 6- or7-membered ring and 1-2 heteroatoms selected from N, O, and S, whereinthe heterocyclyl is optionally substituted with one or more substituentsindependently selected from halogen, OH, and C(O)(C₁-C₃) alkyl. In otherembodiments, at least one R₉ is heterocyclyl comprising a 6- or7-membered ring and 1-2 heteroatoms selected from N, O, and S, whereinthe heterocyclyl is optionally substituted with one to two substituentsindependently selected from halogen, OH, and C(O)(C₁-C₃) alkyl. In otherembodiments, at least one R₉ is piperidinyl, azepinyl, piperazinyl, ormorpholinyl optionally substituted with one to more substituentsindependently selected from halogen, OH, and C(O)(C₁-C₃) alkyl. In otherembodiments, at least one R₉ is piperidinyl, azepinyl, piperazinyl, ormorpholinyl optionally substituted with one to two substituentsindependently selected from OH and C(O)(C₁-C₃) alkyl.

(7a) In some embodiments of Formula (I′), R₇ is H.

(7b) In some embodiments of Formula (I′), R₇ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₇ is methylor ethyl.

(8) In some embodiments of Formula (I′), R₄ is

In other embodiments, R₄ is

In other embodiments, R₄ is

In further embodiments, R₄ is

(9a) In some embodiments of Formula (I′), R₁₀ is (C₁-C₃) alkyloptionally substituted with heterocyclyl comprising a 5- or 6-memberedring and 1-3 heteroatoms selected from N, O, and S. In otherembodiments, R₁₀ is methyl, ethyl, propyl, or i-propyl, wherein themethyl, ethyl, propyl, or i-propyl is optionally substituted withheterocyclyl comprising a 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S. In other embodiments, R₁₀ is methyl or ethyl,wherein the methyl or ethyl is optionally substituted with heterocyclylcomprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N,O, and S. In other embodiments, R₁₀ is methyl or ethyl. In otherembodiments, R₁₀ is methyl or ethyl, wherein the methyl or ethyl isoptionally substituted with heterocyclyl comprising a 6-membered ringand 1-3 heteroatoms selected from N, O, and S. In other embodiments, R₁₀is methyl or ethyl, wherein the methyl or ethyl is optionallysubstituted with heterocyclyl comprising a 6-membered ring and 1-2heteroatoms selected from N, O, and S. In other embodiments, R₁₀ ismethyl or ethyl, wherein the methyl or ethyl is optionally substitutedwith morpholinyl, piperazinyl, or piperidinyl. In other embodiments, R₁₀is methyl or ethyl, wherein the methyl or ethyl is substituted withmorpholinyl, piperazinyl, or piperidinyl. In other embodiments, R₁₀ ismethyl or ethyl, wherein the methyl or ethyl is optionally substitutedwith morpholinyl. In further embodiments, R₁₀ is methyl or ethylsubstituted with morpholinyl.

(9b) In some embodiments of Formula (I′), R₁₀ is (C₁-C₃) alkyloptionally substituted with C(O)NH—(C₁-C₃) alkyl or C(O)N((C₁-C₃)alkyl)₂. In other embodiments, R₁₀ is methyl, ethyl, propyl, ori-propyl, wherein the methyl, ethyl, propyl, or i-propyl is optionallysubstituted with C(O)NH—(C₁-C₃) alkyl or C(O)N((C₁-C₃) alkyl)₂. In otherembodiments, R₁₀ is methyl, ethyl, propyl, or i-propyl, wherein themethyl, ethyl, propyl, or i-propyl is optionally substituted withC(O)NH—(C₁-C₃) alkyl. In other embodiments, R₁₀ is methyl, ethyl,propyl, or i-propyl, wherein the methyl, ethyl, propyl, or i-propyl isoptionally substituted with C(O)N((C₁-C₃) alkyl)₂. In other embodiments,R₁₀ is methyl or ethyl, wherein the methyl or ethyl is optionallysubstituted with C(O)NH—(C₁-C₃) alkyl or C(O)N((C₁-C₃) alkyl)₂. In otherembodiments, R₁₀ is methyl or ethyl, wherein the methyl or ethyl isoptionally substituted with C(O)NH—(C₁-C₃) alkyl. In other embodiments,R₁₀ is methyl or ethyl, wherein the methyl or ethyl is optionallysubstituted with C(O)N((C₁-C₃) alkyl)₂.

(9c) In some embodiments of Formula (I′), R₁₀ is heterocyclyl comprisinga 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S,optionally substituted with one or more (C₁-C₃) alkyl (e.g., methyl,ethyl, propyl, or i-propyl). In other embodiments, R₁₀ is selected frompyrrolidinyl, pyrazolidinyl, imidazolidinyl, triazolidinyl,oxazolidinyl, isoxazolidinyl, oxadiazolidinyl, dioxazolidinyl,thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, dithiazolidinyl,piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl,and morpholinyl, each of which is optionally substituted with one ormore (C₁-C₃) alkyl (e.g., methyl, ethyl, propyl, or i-propyl). In otherembodiments, R₁₀ is pyrrolidinyl, pyrazolidinyl, imidazolidinyl,piperidinyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with one or more (C₁-C₃) alkyl (e.g., methyl, ethyl, propyl,or i-propyl). In other embodiments, R₁₀ is pyrrolidinyl or piperidinyl,each of which is optionally substituted with one or more (C₁-C₃) alkyl(e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments, R₁₀ ispyrrolidinyl or piperidinyl, each of which is optionally substitutedwith methyl.

(10a) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₃)alkyl (e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments,at least one R₁₁ is methyl or ethyl. In further embodiments, at leastone R₁₁ is methyl.

(10b) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₃)haloalkyl (e.g., CH₂F, CHF₂, or CF₃). In other embodiments, at least oneR₁₁ is CH₂F, CHF₂, or CF₃. In further embodiments, at least one R₁₁ isCF₃.

(10c) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₃)alkoxy (e.g., methoxy, ethoxy, propoxy, or i-propoxy). In furtherembodiments, at least one R₁₁ is methoxy.

(10d) In some embodiments of Formula (I′), at least one R₁₁ is (C₁-C₃)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃). In other embodiments, at leastone R₁₁ is OCH₂F, OCHF₂, or OCF₃. In further embodiments, at least oneR₁₁ is OCF₃.

(10e) In some embodiments of Formula (I′), at least one R₁₁ is halogen(e.g., F, Cl, Br, or I). In other embodiments, at least one R₁₁ is F orCl. In other embodiments, at least one R₁₁ is F. In other embodiments,at least one R₁₁ is Cl.

(11a) In some embodiments of Formula (I′), n is 0, 1, or 2. In otherembodiments, n is 0 or 1. In other embodiments, n is 1 or 2.

(11b) In some embodiments of Formula (I′), n is 0.

(11c) In some embodiments of Formula (I′), n is 1.

(11d) In some embodiments of Formula (I′), n is 2.

(13a) In some embodiments of Formula (I′), R₅ is H.

(13b) In some embodiments of Formula (I′), R₅ is (C₁-C₃) alkyl. (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₅ is methylor ethyl. In other embodiments, R₅ is methyl.

In some embodiments of Formula (I′), when R₂, R₅ and R₇ are each H, R₆is ethenyl, and R₄ is

then R₁ is not unsubstituted phenyl.

In some embodiments of Formula (I′), each of the substituents definedfor any one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and n canbe combined with any of the substituents defined for the remainder ofR₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and n.

(14) In some embodiments of Formula (I′), R₅ is as defined in (13a).

(15) In some embodiments of Formula (I′), R₅ is as defined in (13a) andR₁ is as defined in (1a).

(16) In some embodiments of Formula (I′), R₅ is as defined in (13a) andR₁ is as defined in (1b).

(17) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), and n is as defined in (11b).

(18) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), and R₃ is as defined in(4).

(19) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), and R₄ is as defined in (8).

(20) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in any one of(9a)-(9c).

(21) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),and R₈ is as defined in (2a).

(22) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), and R₇ is as defined in (7a).

(23) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), and R₆ is as definedin (5a).

(24) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3a).

(25) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ is as definedin (3a).

(26) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3b).

(27) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ is as definedin (3b).

(28) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), and R₆ is as definedin (5b).

(29) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6a).

(30) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(31) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3a).

(32) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(33) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3b).

(34) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6b).

(35) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(36) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3a).

(37) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(38) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3b).

(39) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), and R₃ is as defined in(4).

(40) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), and R₄ is as defined in (8).

(41) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in any one of(9a)-(9c).

(42) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),and R₈ is as defined in (2a).

(43) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), and R₇ is as defined in (7a).

(44) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), and R₆ is as definedin (5a).

(45) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3a).

(46) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ is as definedin (3a).

(47) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3b).

(48) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ is as definedin (3b).

(49) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), and R₆ is as definedin (5b).

(50) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6a).

(51) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(52) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3a).

(53) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(54) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3b).

(55) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6b).

(56) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(57) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3a).

(58) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₈ is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(59) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3b).

(60) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), and R₃ is as defined in(4).

(61) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), and R₄ is as defined in (8).

(62) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in any one of(9a)-(9c).

(63) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),and R₁₁ is as defined in (10a).

(64) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), and R₈ is as defined in (2a).

(65) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), and R₇ is asdefined in (7a).

(66) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5a).

(67) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3a).

(68) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3a).

(69) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3b).

(70) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3b).

(71) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5b).

(72) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6a).

(73) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3a).

(74) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(75) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3b).

(76) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(77) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6b).

(78) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3a).

(79) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(80) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3b).

(81) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(82) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),and R₁₁ is as defined in (10b).

(83) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), and R₈ is as defined in (2a).

(84) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), and R₇ is asdefined in (7a).

(85) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5a).

(86) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3a).

(87) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3a).

(88) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3b).

(89) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3b).

(90) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5b).

(91) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6a).

(92) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3a).

(93) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(94) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3b).

(95) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(96) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6b).

(97) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3a).

(98) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(99) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3b).

(100) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(101) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), and R₃ is as defined in(4).

(102) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), and R₄ is as defined in (8).

(103) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in any one of(9a)-(9c).

(104) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),and R₁₁ is as defined in (10a).

(105) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), and R₈ is as defined in (2a).

(106) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), and R₇ is asdefined in (7a).

(107) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5a).

(108) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3a).

(109) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3a).

(110) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3b).

(111) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3b).

(112) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5b).

(113) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6a).

(114) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3a).

(115) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(116) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3b).

(117) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(118) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6b).

(119) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3a).

(120) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(121) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3b).

(122) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10a), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(123) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),and R₁₁ is as defined in (10b).

(124) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), and R₈ is as defined in (2a).

(125) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), and R₇ is asdefined in (7a).

(126) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5a).

(127) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3a).

(128) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3a).

(129) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3b).

(130) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5a), and R₂ is as defined in (3b).

(131) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), and R₆ is as defined in (5b).

(132) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6a).

(133) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3a).

(134) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(135) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3b).

(136) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(137) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), and R₉ is as defined in (6b).

(138) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3a).

(139) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(140) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₈ is as defined in (2a), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3b).

(141) In some embodiments of Formula (I′), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in any one of (9a)-(9c),R₁₁ is as defined in (10b), R₇ is as defined in (7a), R₆ is as definedin (5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(142) In some embodiments of Formula (I′), R₁ is as defined in (1a) andR₈ is as defined in (2a).

(143) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), and R₇ is as defined in (7a).

(144) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5a).

(145) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3a).

(146) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3a).

(147) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3b).

(148) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3b).

(149) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5b).

(150) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6a).

(151) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(152) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3a).

(153) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(154) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3b).

(155) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6b).

(156) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(157) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3a).

(158) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(159) In some embodiments of Formula (I′), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3b).

(160) In some embodiments of Formula (I′), R₁ is as defined in (1b) andR₈ is as defined in (2a).

(161) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), and R₇ is as defined in (7a).

(162) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5a).

(163) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3a).

(164) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3a).

(165) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3b).

(166) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3b).

(167) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5b).

(168) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6a).

(169) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(170) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3a).

(171) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(172) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3b).

(173) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6b).

(174) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(175) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3a).

(176) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(177) In some embodiments of Formula (I′), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3b).

In some embodiments of Formula (I′), R₁ is phenyl optionally substitutedwith one or more R₈. In some embodiments of Formula (I′), R₁ is phenylsubstituted with a halogen. In some embodiments of Formula (I′), R₁ isphenyl substituted with F.

In some embodiments of Formula (I′), R₁ is unsubstituted phenyl.

In some embodiments of Formula (I′), R₁ is pyridinyl optionallysubstituted with one or more R₈. In some embodiments of Formula (I′), R₁is unsubstituted pyridinyl.

In some embodiments of Formula (I′), R₁ is benzothiophenyl optionallysubstituted with one or more R₈. In some embodiments of Formula (I′), R₁is benzothiophenyl substituted with a halogen. In some embodiments ofFormula (I′), R₁ is benzothiophenyl substituted with F.

In some embodiments of Formula (I′), R₁ is unsubstitutedbenzothiophenyl.

In some embodiments of Formula (I′), R₂ is H.

In some embodiments of Formula (I′), R₂ is methyl. In some embodimentsof Formula (I′), R₂ is S-methyl. In some embodiments of Formula (I′), R₂is R-methyl.

In some embodiments of Formula (I′), R₃ is

In some embodiments of Formula (I′), R₆ is ethenyl.

In some embodiments of Formula (I′), R₆ is ethenyl substituted with oneor more R₉.

In some embodiments of Formula (I′), R₇ is H.

In some embodiments of Formula (I′), R₅ is H.

In some embodiments of Formula (I′), R₅ and R₇ are each H.

In some embodiments of Formula (I′), R₄ is

In some embodiments, R₁₀ is unsubstituted methyl.

In some embodiments of Formula (I′), R₄ is

In some embodiments, R₁₀ is unsubstituted methyl.

In some embodiments of Formula (I′), R₈ is halogen.

In some embodiments of Formula (I′), R₈ is F.

In some embodiments of Formula (I′), R₁₀ is methyl or ethyl substitutedwith morpholino.

In some embodiments, the compounds of Formula (I′) have the structure ofFormula (I):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₁, and n are each as defined inFormula (I′); and

R₁₀ is (C₁-C₃) alkyl optionally substituted with a heterocyclylcomprising a 5- or 6-membered ring and 1-3 heteroatoms selected from N,O, and S;

provided that when R₂, R₅ and R₇ are each H, R₆ is ethenyl, and R₄ is

then R₁ is not unsubstituted phenyl.

(1a) In some embodiments of Formula (I), R₁ is phenyl optionallysubstituted with one or more R₈. In other embodiments, R₁ is phenyloptionally substituted with one to three R₈. In other embodiments, R₁ isphenyl substituted with at least one R₈, wherein the at least one R₈ isat the ortho position. In other embodiments, R₁ is phenyl substitutedwith at least one R₈, wherein the at least one R₈ is at the metaposition. In other embodiments, R₁ is phenyl substituted with at leastone R₈, wherein the at least one R₈ is at the para position. In otherembodiments, R₁ is phenyl.

(1b) In some embodiments of Formula (I), R₁ is heteroaryl comprising oneor two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O,and S, optionally substituted with one or more R₈. In other embodiments,R₁ is heteroaryl comprising one 5- or 6-membered ring and 1-4heteroatoms selected from N, O, and S, optionally substituted with oneor more R₈. In other embodiments, R₁ is heteroaryl comprising two 5- or6-membered rings and 1-4 heteroatoms selected from N, O, and S,optionally substituted with one or more R₈. In other embodiments, R₁ ispyridinyl or benzothiophenyl optionally substituted with one or more R₈.In other embodiments, R₁ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, orbenzothiophenyl optionally substituted with one or more R₈. In otherembodiments, R₁ is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl,

optionally substituted with one to three R₈. In further embodiments, R₁is 2-pyridinyl, 3-pyridinyl,

optionally substituted with one to three R₈.

(2a) In some embodiments of Formula (I), at least one R₈ is halogen(e.g., F, Cl, Br, or I). In some embodiments, at least one R₈ is F orCl.

(2b) In some embodiments of Formula (I), at least one R₈ is (C₁-C₃)alkyl (e.g., methyl, ethyl, propyl, or i-propyl).

(2c) In some embodiments of Formula (I), at least one R₈ is (C₁-C₃)haloalkyl (e.g., CH₂F, CHF₂, or CF₃).

(2d) In some embodiments of Formula (I), at least one R₈ is OH, NH₂,NH(C₁-C₃) alkyl, or N((C₁-C₃) alkyl)₂. In other embodiments, at leastone R₈ is OH or NH₂. In other embodiments, at least one R₈ is NH(C₁-C₃)alkyl (e.g., methylamino, ethylamino, propylamino, or i-propylamino) orN((C₁-C₃) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordii-propylamino).

(3a) In some embodiments of Formula (I), R₂ is H.

(3b) In some embodiments of Formula (I), R₂ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₂ is methylor ethyl. In further embodiments, R₂ is methyl. In further embodiments,R₂ is in the S-configuration or R-configuration. In further embodiments,R₂ is in the S-methyl or R-methyl.

(4) In some embodiments of Formula (I), R₃ is

(5a) In some embodiments of Formula (I), R₆ is (C₂-C₄) alkenyl (e.g.,ethenyl, propenyl, or butenyl). In other embodiments, R₆ is ethenyl orpropenyl. In further embodiments, R₆ is ethenyl.

(5b) In some embodiments of Formula (I), R₆ is (C₂-C₄) alkenyl (e.g.,ethenyl, propenyl, or butenyl) substituted with one or more R₉. In otherembodiments, R₆ is ethenyl or propenyl substituted with one or more R₉.In further embodiments, R₆ is

(6a) In some embodiments of Formula (I), at least one R₉ is NH₂,NH(C₁-C₃) alkyl, or N((C₁-C₃) alkyl)₂. In other embodiments, at leastone R₉ is NH₂. In other embodiments, at least one R₉ is NH(C₁-C₃) alkyl(e.g., methylamino, ethylamino, propylamino, or i-propylamino) orN((C₁-C₃) alkyl)₂ (e.g., dimethylamino, diethylamino, dipropylamino, ordii-propylamino). In other embodiments, at least one R₉ is methylamino,ethylamino, dimethylamino, or diethylamino. In other embodiments, atleast one R₉ is dimethylamino or diethylamino. In further embodiments,at least one R₉ is dimethylamino.

(6b) In some embodiments of Formula (I), at least one R₉ is heterocyclylcomprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N,O, and S, wherein the heterocyclyl is optionally substituted with one ormore substituents independently selected from halogen (e.g., F, Cl, Br,or I), OH, and C(O)(C₁-C₃) alkyl (e.g., C(O)CH₃, C(O)CH₂CH₃,C(O)CH₂CH₂CH₃, or C(O)CH(CH₃)₂). In other embodiments, at least one R₉is heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one to two substituents independently selected fromhalogen, OH, and C(O)(C₁-C₃) alkyl. In other embodiments, at least oneR₉ is heterocyclyl comprising a 6- or 7-membered ring and 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more substituents independentlyselected from halogen, OH, and C(O)(C₁-C₃) alkyl. In other embodiments,at least one R₉ is heterocyclyl comprising a 6- or 7-membered ring and1-2 heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more substituents independentlyselected from halogen, OH, and C(O)(C₁-C₃) alkyl. In other embodiments,at least one R₉ is heterocyclyl comprising a 6- or 7-membered ring and1-2 heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one to two substituents independentlyselected from halogen, OH, and C(O)(C₁-C₃) alkyl. In other embodiments,at least one R₉ is piperidinyl, azepinyl, piperazinyl, or morpholinyloptionally substituted with one to more substituents independentlyselected from halogen, OH, and C(O)(C₁-C₃) alkyl. In other embodiments,at least one R₉ is piperidinyl, azepinyl, piperazinyl, or morpholinyloptionally substituted with one to two substituents independentlyselected from OH and C(O)(C₁-C₃) alkyl.

(7a) In some embodiments of Formula (I), R₇ is H.

(7b) In some embodiments of Formula (I), R₇ is (C₁-C₃) alkyl (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₇ is methylor ethyl.

(8) In some embodiments of Formula (I), R₄ is

In other embodiments, R₄ is

In other embodiments, R₄ is

In further embodiments, R₄ is

(9) In some embodiments of Formula (I), R₁₀ is (C₁-C₃) alkyl optionallysubstituted with heterocyclyl comprising a 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S. In other embodiments, R₁₀ ismethyl, ethyl, propyl, or i-propyl, wherein the methyl, ethyl, propyl,or i-propyl is optionally substituted with heterocyclyl comprising a 5-or 6-membered ring and 1-3 heteroatoms selected from N, O, and S. Inother embodiments, R₁₀ is methyl or ethyl, wherein the methyl or ethylis optionally substituted with heterocyclyl comprising a 5- or6-membered ring and 1-3 heteroatoms selected from N, O, and S. In otherembodiments, R₁₀ is methyl or ethyl. In other embodiments, R₁₀ is methylor ethyl, wherein the methyl or ethyl is optionally substituted withheterocyclyl comprising a 6-membered ring and 1-3 heteroatoms selectedfrom N, O, and S. In other embodiments, R₁₀ is methyl or ethyl, whereinthe methyl or ethyl is optionally substituted with heterocyclylcomprising a 6-membered ring and 1-2 heteroatoms selected from N, O, andS. In other embodiments, R₁₀ is methyl or ethyl, wherein the methyl orethyl is optionally substituted with morpholinyl, piperazinyl, orpiperidinyl. In other embodiments, R₁₀ is methyl or ethyl, wherein themethyl or ethyl is substituted with morpholinyl, piperazinyl, orpiperidinyl. In other embodiments, R₁₀ is methyl or ethyl, wherein themethyl or ethyl is optionally substituted with morpholinyl. In furtherembodiments, R₁₀ is methyl or ethyl substituted with morpholinyl.

(10a) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₃)alkyl (e.g., methyl, ethyl, propyl, or i-propyl). In other embodiments,at least one R₁₁ is methyl or ethyl. In further embodiments, at leastone R₁₁ is methyl.

(10b) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₃)haloalkyl (e.g., CH₂F, CHF₂, or CF₃). In other embodiments, at least oneR₁₁ is CH₂F, CHF₂, or CF₃. In further embodiments, at least one R₁₁ isCF₃.

(10c) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₃)alkoxy (e.g., methoxy, ethoxy, propoxy, or i-propoxy). In furtherembodiments, at least one R₁₁ is methoxy.

(10d) In some embodiments of Formula (I), at least one R₁₁ is (C₁-C₃)haloalkoxy (e.g., OCH₂F, OCHF₂, or OCF₃). In other embodiments, at leastone R₁₁ is OCH₂F, OCHF₂, or OCF₃. In further embodiments, at least oneR₁₁ is OCF₃.

(10e) In some embodiments of Formula (I), at least one R₁₁ is halogen(e.g., F, Cl, Br, or I). In other embodiments, at least one R₁₁ is F orCl. In other embodiments, at least one R₁₁ is F. In other embodiments,at least one R₁₁ is Cl.

(11a) In some embodiments of Formula (I), n is 0, 1, or 2. In otherembodiments, n is 0 or 1. In other embodiments, n is 1 or 2.

(11b) In some embodiments of Formula (I), n is 0.

(11c) In some embodiments of Formula (I), n is 1.

(11d) In some embodiments of Formula (I), n is 2.

(13a) In some embodiments of Formula (I), R₅ is H.

(13b) In some embodiments of Formula (I), R₅ is (C₁-C₃) alkyl. (e.g.,methyl, ethyl, propyl, or i-propyl). In other embodiments, R₅ is methylor ethyl. In other embodiments, R₅ is methyl.

In some embodiments of Formula (I), when R₂, R₅ and R₇ are each H, R₆ isethenyl, and R₄ is

then R₁ is not unsubstituted phenyl.

In some embodiments of Formula (I), each of the substituents defined forany one of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and n can becombined with any of the substituents defined for the remainder of R₁,R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and n.

(14) In some embodiments of Formula (I), R₅ is as defined in (13a).

(15) In some embodiments of Formula (I), R₅ is as defined in (13a) andR₁ is as defined in (1a).

(16) In some embodiments of Formula (I), R₅ is as defined in (13a) andR₁ is as defined in (1b).

(17) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), and n is as defined in (11b).

(18) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), and R₃ is as defined in(4).

(19) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), and R₄ is as defined in (8).

(20) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in (9).

(21) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), and R₈ is asdefined in (2a).

(22) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), and R₇ is as defined in (7a).

(23) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), and R₆ is as defined in (5a).

(24) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ isas defined in (3a).

(25) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3a).

(26) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ isas defined in (3b).

(27) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3b).

(28) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), and R₆ is as defined in (5b).

(29) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), and R₉ isas defined in (6a).

(30) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6a), and R₂ is as defined in (3a).

(31) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3a).

(32) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6a), and R₂ is as defined in (3b).

(33) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3b).

(34) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), and R₉ isas defined in (6b).

(35) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6b), and R₂ is as defined in (3a).

(36) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3a).

(37) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6b), and R₂ is as defined in (3b).

(38) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3b).

(39) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), and R₃ is as defined in(4).

(40) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), and R₄ is as defined in (8).

(41) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in (9).

(42) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), and R₈ is asdefined in (2a).

(43) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), and R₇ is as defined in (7a).

(44) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), and R₆ is as defined in (5a).

(45) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ isas defined in (3a).

(46) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3a).

(47) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5a), and R₂ isas defined in (3b).

(48) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5a), and R₂ is as defined in (3b).

(49) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), and R₆ is as defined in (5b).

(50) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), and R₉ isas defined in (6a).

(51) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6a), and R₂ is as defined in (3a).

(52) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3a).

(53) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6a), and R₂ is as defined in (3b).

(54) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6a), and R₂ isas defined in (3b).

(55) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), and R₉ isas defined in (6b).

(56) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6b), and R₂ is as defined in (3a).

(57) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3a).

(58) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₈ is as definedin (2a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉ is asdefined in (6b), and R₂ is as defined in (3b).

(59) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11b), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₇ is as definedin (7a), R₆ is as defined in (5b), R₉ is as defined in (6b), and R₂ isas defined in (3b).

(60) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), and R₃ is as defined in(4).

(61) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), and R₄ is as defined in (8).

(62) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in (9).

(63) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), and R₁₁ is asdefined in (10a).

(64) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), and R₈ is as defined in (2a).

(65) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), and R₇ is as defined in(7a).

(66) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5a).

(67) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3a).

(68) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3a).

(69) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3b).

(70) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3b).

(71) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5b).

(72) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6a).

(73) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3a).

(74) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3a).

(75) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3b).

(76) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3b).

(77) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6b).

(78) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3a).

(79) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3a).

(80) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3b).

(81) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3b).

(82) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), and R₁₁ is asdefined in (10b).

(83) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), and R₈ is as defined in (2a).

(84) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), and R₇ is as defined in(7a).

(85) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5a).

(86) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3a).

(87) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3a).

(88) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3b).

(89) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3b).

(90) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5b).

(91) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6a).

(92) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3a).

(93) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3a).

(94) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3b).

(95) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3b).

(96) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6b).

(97) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3a).

(98) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3a).

(99) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3b).

(100) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1a), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3b).

(101) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), and R₃ is as defined in(4).

(102) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), and R₄ is as defined in (8).

(103) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), and R₁₀ is as defined in (9).

(104) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), and R₁₁ is asdefined in (10a).

(105) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), and R₈ is as defined in (2a).

(106) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), and R₇ is as defined in(7a).

(107) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5a).

(108) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3a).

(109) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3a).

(110) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3b).

(111) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3b).

(112) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5b).

(113) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6a).

(114) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3a).

(115) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3a).

(116) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3b).

(117) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3b).

(118) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6b).

(119) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3a).

(120) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3a).

(121) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3b).

(122) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10a), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3b).

(123) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), and R₁₁ is asdefined in (10b).

(124) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), and R₈ is as defined in (2a).

(125) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), and R₇ is as defined in(7a).

(126) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5a).

(127) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3a).

(128) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3a).

(129) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5a), and R₂ is as defined in (3b).

(130) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5a),and R₂ is as defined in (3b).

(131) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a),and R₆ is as defined in (5b).

(132) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6a).

(133) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3a).

(134) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3a).

(135) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6a), and R₂ is as defined in(3b).

(136) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6a), and R₂ is as defined in (3b).

(137) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), and R₉ is as defined in (6b).

(138) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3a).

(139) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3a).

(140) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₈ is as defined in (2a), R₇ is as defined in (7a), R₆is as defined in (5b), R₉ is as defined in (6b), and R₂ is as defined in(3b).

(141) In some embodiments of Formula (I), R₅ is as defined in (13a), R₁is as defined in (1b), n is as defined in (11c), R₃ is as defined in(4), R₄ is as defined in (8), R₁₀ is as defined in (9), R₁₁ is asdefined in (10b), R₇ is as defined in (7a), R₆ is as defined in (5b), R₉is as defined in (6b), and R₂ is as defined in (3b).

(142) In some embodiments of Formula (I), R₁ is as defined in (1a) andR₈ is as defined in (2a).

(143) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), and R₇ is as defined in (7a).

(144) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5a).

(145) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3a).

(146) In some embodiments of Formula (I), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3a).

(147) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3b).

(148) In some embodiments of Formula (I), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3b).

(149) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5b).

(150) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6a).

(151) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(152) In some embodiments of Formula (I), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3a).

(153) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(154) In some embodiments of Formula (I), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3b).

(155) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6b).

(156) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(157) In some embodiments of Formula (I), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3a).

(158) In some embodiments of Formula (I), R₁ is as defined in (1a), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(159) In some embodiments of Formula (I), R₁ is as defined in (1a), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3b).

(160) In some embodiments of Formula (I), R₁ is as defined in (1b) andR₈ is as defined in (2a).

(161) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), and R₇ is as defined in (7a).

(162) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5a).

(163) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3a).

(164) In some embodiments of Formula (I), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3a).

(165) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5a), and R₂ is as defined in (3b).

(166) In some embodiments of Formula (I), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5a), and R₂ is as defined in(3b).

(167) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), and R₆ is as defined in(5b).

(168) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6a).

(169) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3a).

(170) In some embodiments of Formula (I), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3a).

(171) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6a), and R₂ is as defined in (3b).

(172) In some embodiments of Formula (I), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6a), and R₂ is as defined in (3b).

(173) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), and R₉ is as defined in (6b).

(174) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3a).

(175) In some embodiments of Formula (I), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3a).

(176) In some embodiments of Formula (I), R₁ is as defined in (1b), R₈is as defined in (2a), R₇ is as defined in (7a), R₆ is as defined in(5b), R₉ is as defined in (6b), and R₂ is as defined in (3b).

(177) In some embodiments of Formula (I), R₁ is as defined in (1b), R₇is as defined in (7a), R₆ is as defined in (5b), R₉ is as defined in(6b), and R₂ is as defined in (3b).

In some embodiments of Formula (I), R₁ is phenyl optionally substitutedwith one or more R₈. In some embodiments of Formula (I), R₁ is phenylsubstituted with a halogen. In some embodiments of Formula (I), R₁ isphenyl substituted with F.

In some embodiments of Formula (I), R₁ is unsubstituted phenyl.

In some embodiments of Formula (I), R₁ is pyridinyl optionallysubstituted with one or more R₈. In some embodiments of Formula (I), R₁is unsubstituted pyridinyl.

In some embodiments of Formula (I), R₁ is benzothiophenyl optionallysubstituted with one or more R₈. In some embodiments of Formula (I), R₁is benzothiophenyl substituted with a halogen. In some embodiments ofFormula (I), R₁ is benzothiophenyl substituted with F.

In some embodiments of Formula (I), R₁ is unsubstituted benzothiophenyl.

In some embodiments of Formula (I), R₂ is H.

In some embodiments of Formula (I), R₂ is methyl. In some embodiments ofFormula (I), R₂ is S-methyl. In some embodiments of Formula (I), R₂ isR-methyl.

In some embodiments of Formula (I), R₃ is

In some embodiments of Formula (I), R₆ is ethenyl.

In some embodiments of Formula (I), R₆ is ethenyl substituted with oneor more R₉.

In some embodiments of Formula (I), R₇ is H.

In some embodiments of Formula (I), R₅ is H.

In some embodiments of Formula (I), R₅ and R₇ are each H.

In some embodiments of Formula (I), R₄ is

In some embodiments, R₁₀ is unsubstituted methyl.

In some embodiments of Formula (I), R₄ is

In some embodiments, R₁₀ is unsubstituted methyl.

In some embodiments of Formula (I), R₈ is halogen.

In some embodiments of Formula (I), R₈ is F.

In some embodiments of Formula (I), R₁₀ is methyl or ethyl substitutedwith morpholino.

In some embodiments, the compounds of Formula (I′) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (I′).

In some embodiments, the compounds of Formula (I′) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (I′).

In some embodiments, the compounds of Formula (I) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (I).

In some embodiments, the compounds of Formula (I) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (I).

In some embodiments, the compounds of Formula (I′) or (I) have thestructure of Formula (Ia) or (Ib):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein:

R₁ is phenyl or heteroaryl comprising one or two 5- or 6-membered ringsand 1-4 heteroatoms selected from N, O, and S, wherein the phenyl orheteroaryl is optionally substituted with one or more R₈;

each R₈ is independently halogen, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl,(C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, OH, NH₂, NH(C₁-C₃) alkyl, orN((C₁-C₃) alkyl)₂;

R₂ is H or (C₁-C₃) alkyl;

R₆ is (C₂-C₄) alkenyl optionally substituted with one or more R₉;

each R₉ is independently NH₂, NH(C₁-C₃) alkyl, N((C₁-C₃) alkyl)₂, orheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more substituents independently selected fromhalogen, OH, and C(O)(C₁-C₃) alkyl;

R₇ is H or (C₁-C₃) alkyl;

R₁₀ is (C₁-C₃) alkyl optionally substituted with heterocyclyl comprisinga 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S;

each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃)alkoxy, (C₁-C₃) haloalkoxy, or halogen; and

n is 0, 1, or 2;

provided that when R₂ and R₇ are each H, and R₆ is ethenyl in Formula(Ib), then R₁ is not unsubstituted phenyl.

In some embodiments of Formulae (Ia)-(Ib), each of the substituentsdefined for any one of R₁, R₂, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and n can becombined with any of the substituents defined for the remainder of R₁,R₂, R₆, R₇, R₈, R₉, R₁₀, R₁₁, and n.

In some embodiments of Formulae (Ia)-(Ib), each of R₁, R₂, R₆, R₇, R₈,R₉, R₁₀, R₁₁, and n can be any substituent selected from the groupsdefined above in Formula (I′) or (I), and can be combined with oneanother described above in Formula (I′) or (I) (e.g., (1a)-(177)).

In some embodiments of Formulae (Ia)-(Ib), when R₂ and R₇ are each H, R₆is ethenyl, n is 0, and R₁₀ is methyl or —CH₂CH₂morpholinyl, then R₁ isnot unsubstituted phenyl.

In some embodiments, the compounds of Formula (Ia) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (Ia).

In some embodiments, the compounds of Formula (Ia) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (Ia).

In some embodiments, the compounds of Formula (Ib) have the followingstructure

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (Ib).

In some embodiments, the compounds of Formula (Ib) have the followingstructure:

wherein R₂ is (C₁-C₃) alkyl and the other variable are as defined abovefor Formula (Ib).

In some embodiments of Formulae (Ia)-(Ib), each of the substituentsdefined for any one of R₁, R₂, R₃, R₆, R₇, R₈, R₉, R₁₀, and R₁₁ can becombined with any of the substituents defined for the remainder of R₁,R₂, R₃, R₆, R₇, R₈, R₉, R₁₀, and R₁₁.

Non-limiting illustrative compounds of the application include:

Compound Number Example Compound Name I-1 

benzyl (3-acrylamidophenyl)(2-((1- methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate I-2 

3-fluorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-3 

3-fluorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-4 

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-5 

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-6 

benzo[b]thiophen-2-ylmethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-7 

benzo[b]thiophen-2-ylmethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-8 

4-chlorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-9 

4-chlorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-10

(5-fluoropyridin-2-yl)methyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-11

(5-fluoropyridin-2-yl)methyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-12

(6-fluoropyridin-3-yl)methyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-13

(6-fluoropyridin-3-yl)methyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-14

(R)-1-(4-fluorophenyl)ethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-15

(R)-1-(4-fluorophenyl)ethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-16

(S)-1-(4-fluorophenyl)ethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-17

(S)-1-(4-fluorophenyl)ethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-18

benzo[b]thiophen-3-ylmethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4- yl)carbamate I-19

benzo[b]thiophen-3-ylmethyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-20

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-(2-morpholinoethyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)carbamate I-21

4-fluorobenzyl (3- acrylamidophenyl)(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-22

4-fluorobenzyl (3- acrylamidophenyl)(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-23

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)carbamate I-24

4-fluorobenzyl (E)-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(3- (4-(piperidin-1-yl)but-2-enamido)phenyl)carbamate I-25

4-fluorobenzyl (E)-(3-(4-(4- hydroxypiperidin-1-yl)but-2-enamido)phenyl)(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate I-26

4-fluorobenzyl (E)-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(3- (4-morpholinobut-2-enamido)phenyl)carbamate I-27

4-fluorobenzyl (E)-(3-(4-(azepan-1- yl)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)carbamate I-28

4-fluorobenzyl (E)-(3-(4- (dimethylamino)but-2-enamido)phenyl)(2-((1-methyl-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate I-29

2,4-difluorobenzyl (3- acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4- yl)carbamate I-30

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)carbamateI-31

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-(2-(methylamino)-2-oxoethyl)-1H- pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate I-32

4-fluorobenzyl (3- acrylamidophenyl)(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4- yl)amino)pyrimidin-4-yl)carbamate

The compounds of the application are capable of modulating EGFRactivity. In some embodiments, the compounds of the present applicationare capable of inhibiting or decreasing EGFR activity.

In some embodiments, the compounds of the present application arecapable of modulating (e.g., inhibiting or decreasing) the activity ofEGFR containing one or more mutations. In some embodiments, the mutantEGFR contains one or more mutations selected from T790M, L718Q, L844V,L858R, Del, D770delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, insYVMA, H773dupH, A763_Y764insFQEA, H773_V774insNPH,V774_C775insHV, N771_P772insV, D770_N771insGL, N771delinsGY, andH773_V774insAH. In other embodiments, the mutant EGFR contains acombination of mutations, wherein the combination is selected fromDel/L718Q, Del/L844V, Del/T790M, Del/T790M/L718Q, Del/T790M/L844V,L858R/L718Q, L858R/L844V, L858R/T790M, and L858R/T790M/L718Q. In otherembodiments, the mutant EGFR contains a combination of mutations,wherein the combination is selected from Del/L718Q, Del/L844V,Del/T790M, Del/T790M/L844V, L858R/L844V, and L858R/T790M. In otherembodiments, the mutant EGFR contains a combination of mutations,wherein the combination is selected from L858R/T790M, Del/T790M,Del/T790M/L718Q, and L858R/T790M/L718Q. In further embodiments, themutant EGFR contains one or more mutations selected from D770delinsGY,D770_N771insSVD, V769_D770insASV, Y764_V765insHH, insYVMA, and H773dupH.

In some embodiments, the compounds of the present application arecapable of modulating (e.g., inhibiting or decreasing) the activity ofEGFR containing one or more mutations, but do not affect the activity ofa wild-type EGFR.

Modulation of EGFR containing one or more mutations, such as thosedescribed herein, but not a wild-type EGFR, provides a novel approach tothe treatment, prevention, or amelioration of diseases including, butnot limited to, cancer and metastasis, inflammation, arthritis, systemiclupus erthematosus, skin-related disorders, pulmonary disorders,cardiovascular disease, ischemia, neurodegenerative disorders, liverdisease, gastrointestinal disorders, viral and bacterial infections,central nervous system disorders, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis, spinalcord injury, and peripheral neuropathy.

In some embodiments, the compounds of the application exhibit greaterinhibition of EGFR containing one or more mutations as described hereinrelative to a wild-type EGFR. In certain embodiments, the compounds ofthe application exhibit at least 2-fold, 3-fold, 5-fold, 10-fold,25-fold, 50-fold or 100-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the application exhibit up to1000-fold greater inhibition of EGFR containing one or more mutations asdescribed herein relative to a wild-type EGFR. In various embodiments,the compounds of the application exhibit up to 10000-fold greaterinhibition of EGFR having a mutation selected from D770delinsGY,D770_N771insSVD, V769_D770insASV, Y764_V765insHH, and H773dupH relativeto a wild-type EGFR.

In various embodiments, the compounds of the application exhibit fromabout 2-fold to about 10-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the application exhibit from about10-fold to about 100-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the application exhibit from about100-fold to about 1000-fold greater inhibition of EGFR containing one ormore mutations as described herein relative to a wild-type EGFR. Invarious embodiments, the compounds of the application exhibit from about1000-fold to about 10000-fold greater inhibition of EGFR containing oneor more mutations as described herein relative to a wild-type EGFR.

In certain embodiments, the compounds of the application exhibit atleast 2-fold greater inhibition of EGFR having a mutation selected fromD770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, insYVMA,and H773dupH relative to a wild-type EGFR. In certain embodiments, thecompounds of the application exhibit at least 3-fold greater inhibitionof EGFR having a mutation selected from D770delinsGY, D770_N771insSVD,V769_D770insASV, Y764_V765insHH, insYVMA, and H773dupH relative to awild-type EGFR. In certain embodiments, the compounds of the applicationexhibit at least 5-fold greater inhibition of EGFR having a mutationselected from D770delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, insYVMA, and H773dupH relative to a wild-type EGFR. Incertain embodiments, the compounds of the application exhibit at least10-fold greater inhibition of EGFR having a mutation selected fromD770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, insYVMA,and H773dupH relative to a wild-type EGFR. In certain embodiments, thecompounds of the application exhibit at least 25-fold greater inhibitionof EGFR having a mutation selected from D770delinsGY, D770_N771insSVD,V769_D770insASV, Y764_V765insHH, insYVMA, and H773dupH relative to awild-type EGFR. In certain embodiments, the compounds of the applicationexhibit at least 50-fold greater inhibition of EGFR having a mutationselected from D770delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, insYVMA, and H773dupH relative to a wild-type EGFR. Incertain embodiments, the compounds of the application exhibit at least100-fold greater inhibition of EGFR having a mutation selected fromD770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, insYVMA,and H773dupH relative to a wild-type EGFR.

In some embodiments, the inhibition of EGFR activity is measured byIC₅₀.

In some embodiments, the inhibition of EGFR activity is measured byEC₅₀.

In some embodiments, the compounds of the application covalently modifyCysteine 797 in EGFR.

In some embodiments, the application provides a compound comprising anirreversible kinase inhibitor, wherein the compound is a more potentinhibitor of a drug-resistant EGFR mutant relative to a wild type EGFR.For example, the compound can be at least about 2-fold, 3-fold, 5-fold,10-fold, 25-fold, 50-fold or about 100-fold more potent at inhibitingthe kinase activity of the drug-resistant EGFR mutant relative to awild-type EGFR. In some embodiments, the drug-resistant EGFR mutant isresistant to one or more known EGFR inhibitors, including but notlimited to gefitinib, erlotinib, lapatinib, afatinib, WZ4002

HKI-272, CL-387,785, and AZD9291:

In some embodiments, the drug-resistant EGFR mutant comprises asensitizing mutation, such as Del and L858R. In other embodiments, thedrug-resistant EGFR mutant comprises an exon-20 insertion mutation, suchas 770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, insYVMA, and H773dupH.

In some embodiments, the application provides a compound comprising anirreversible kinase inhibitor, wherein the compound inhibits kinaseactivity of a drug-resistant EGFR mutant harboring a sensitizingmutation (e.g., Del and/or L858R) and a drug-resistance mutation (e.g.,T790M, L718Q, L844V, 770delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, insYVMA, and/or H773dupH) with less than a 10-folddifference in potency (e.g., as measured by IC₅₀) relative to an EGFRmutant harboring the sensitizing mutation but not the drug-resistancemutation. In some embodiments, the difference in potency is less thanabout 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold.

In some embodiments, the application provides a compound comprising anirreversible kinase inhibitor, wherein the compound is more potent thanone or more known EGFR inhibitors, including but not limited togefitinib, erlotinib, afatinib, lapatinib, WZ4002, HKI-272, CL-387,785,and AZD9291, at inhibiting the activity of EGFR containing one or moremutations as described herein, such as T790M, L718Q, L844V, L858R, Del,770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH, ins YVMA,or H773dupH. For example, the compound can be at least about 2-fold,3-fold, 5-fold, 10-fold, 25-fold, 50-fold or about 100-fold more potent(e.g., as measured by IC₅₀) than gefitinib, erlotinib, afatinib,lapatinib, WZ4002, HKI-272, CL-387,785, and AZD9291 at inhibiting theactivity of the EGFR containing one or more mutations as describedherein.

In some embodiments, the application provides a compound comprising anirreversible kinase inhibitor, wherein the compound is less potent thanone or more known EGFR inhibitors, including, but not limited to,gefitinib, erlotinib, afatinib, Neratinib, lapatinib, WZ4002, HKI-272,CL-387,785, and AZD9291, at inhibiting the activity of a wild-type EGFR.For example, the compound can be at least about 2-fold, 3-fold, 5-fold,10-fold, 25-fold, 50-fold or about 100-fold less potent (e.g., asmeasured by IC₅₀) than gefitinib, erlotinib, afatinib, Neratinib,lapatinib, WZ4002, HKI-272, CL-387,785, and AZD9291, at inhibiting theactivity of a wild-type EGFR.

Potency of the inhibitor can be determined by IC₅₀ value. A compoundwith a lower IC₅₀ value, as determined under substantially similarconditions, is a more potent inhibitor relative to a compound with ahigher IC₅₀ value. In some embodiments, the substantially similarconditions comprise determining an EGFR-dependent phosphorylation levelin 3T3 cells expressing a wild type EGFR, a mutant EGFR, or a fragmentof any thereof.

An EGFR sensitizing mutation comprises without limitation L858R, G719S,G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon20. A drug-resistant EGFR mutant can have without limitation a drugresistance mutation comprising T790M, T854A, L718Q, D761Y, 770delinsGY,D770_N771insSVD, V769_D770insASV, Y764_V765insHH, ins YVMA, or H773dupH.

The selectivity between wild-type EGFR and EGFR containing one or moremutations as described herein can also be measured using cellularproliferation assays where cell proliferation is completely dependent onkinase activity. For example, murine Ba/F3 cells transfected with asuitable version of wild-type EGFR (such as VIII; containing a WT EGFRkinase domain), or Ba/F3 cells transfected with L858R/T790M,Del/T790M/L718Q, L858R/T790M/L718Q, Exon 19 deletion/T790M, 770delinsGY,D770_N771insSVD, V769_D770insASV, Y764_V765insHH, ins YVMA, or H773dupHcan be used. Proliferation assays are performed at a range of inhibitorconcentrations (10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM,I nM) and an EC₅₀ is calculated.

An alternative method to measure effects on EGFR activity is to assayEGFR phosphorylation. Wild type or mutant (L858R/T790M, Del/T790M,Del/T790M/L718Q, L858R/T790M/L718Q, 770delinsGY, D770_N771insSVD,V769_D770insASV, Y764_V765insHH, ins YVMA, or H773dupH) EGFR can betransfected into NIH-3T3 cells (which do not normally express endogenousEGFR) and the ability of the inhibitor (using concentrations as above)to inhibit EGFR phosphorylation can be assayed. Cells are exposed toincreasing concentrations of inhibitor for 6 hours and stimulated withEGF for 10 minutes. The effects on EGFR phosphorylation are assayed byWestern Blotting using phospho-specific (Y1068) EGFR antibodies.

In another aspect, the present application relates to a compound thatcovalently modifies Cysteine 797 in EGFR, wherein the compound exhibitsgreater than 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold,100-fold, or 1000-fold inhibition of EGFR containing one or moremutations as described herein (e.g., L858R/T790M, Del/T790M,Del/T790M/L718Q, L858R/T790M/L718Q, 770delinsGY, D770_N771insSVD,V769_D770insASV, Y764_V765insHH, insYVMA, or H773dupH) relative to awild-type EGFR.

Definitions

Listed below are definitions of various terms used to describe thisapplication. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals containing, in certain embodiments,between one and six, or one and eight carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl radicals; and examples of C₁-C₈ alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl, octyl radicals.

The term “alkenyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six, or two to eight carbon atoms having at least one carbon-carbondouble bond. The double bond may or may not be the point of attachmentto another group. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

The term “alkynyl,” as used herein, denotes a monovalent group derivedfrom a hydrocarbon moiety containing, in certain embodiments, from twoto six, or two to eight carbon atoms having at least one carbon-carbontriple bond. The alkynyl group may or may not be the point of attachmentto another group. Representative alkynyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “alkoxy” refers to an —O-alkyl radical.

The term “aryl,” as used herein, refers to a mono- or poly-cycliccarbocyclic ring

system having one or more aromatic rings, fused or non-fused, including,but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl,indenyl and the like.

The term “aralkyl,” as used herein, refers to an alkyl residue attachedto an aryl ring. Examples include, but are not limited to, benzyl,phenethyl and the like.

The term “cycloalkyl,” as used herein, denotes a monovalent groupderived from a monocyclic or polycyclic saturated or partiallyunsaturated carbocyclic ring compound. Examples of C₃-C₈-cycloalkylinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2]octyl. Also contemplated is a monovalent group derived from a monocyclicor polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond by the removal of a single hydrogen atom.Examples of such groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,and the like.

The term “heteroaryl,” as used herein, refers to a mono- or poly-cyclic(e.g., bi-, or tri-cyclic or more) fused or non-fused, radical or ringsystem having at least one aromatic ring, having from five to ten ringatoms of which one ring atoms is selected from S, O, and N; zero, one,or two ring atoms are additional heteroatoms independently selected fromS, O, and N; and the remaining ring atoms are carbon. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroaralkyl,” as used herein, refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylethyl and the like.

The term “heterocyclyl,” or “heterocycloalkyl,” as used herein, refersto a non-aromatic 3-, 4-, 5-, 6- or 7-membered ring or a bi- ortri-cyclic group fused of non-fused system, where (i) each ring containsbetween one and three heteroatoms independently selected from oxygen,sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 double bondsand each 6-membered ring has 0 to 2 double bonds, (iii) the nitrogen andsulfur heteroatoms may optionally be oxidized, (iv) the nitrogenheteroatom may optionally be quaternized, and (v) any of the above ringsmay be fused to a benzene ring. Representative heterocycloalkyl groupsinclude, but are not limited to, [1,3]dioxolane, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “alkylamino” refers to a group having the structure —NH(C₁-C₁₂alkyl) where C₁-C₁₂ alkyl is as previously defined.

The term “dialkylamino” refers to a group having the structure —N(C₁-C₁₂alkyl)₂ where C₁-C₁₂ alkyl is as previously defined.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

In accordance with the application, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The terms “hal,” “halo,” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

As described herein, compounds of the application may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the application. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. The terms “optionally substituted”, “optionally substitutedalkyl,” “optionally substituted “optionally substituted alkenyl,”“optionally substituted alkynyl”, “optionally substituted cycloalkyl,”“optionally substituted cycloalkenyl,” “optionally substituted aryl”,“optionally substituted heteroaryl,” “optionally substituted aralkyl”,“optionally substituted heteroaralkyl,” “optionally substitutedheterocycloalkyl,” and any other optionally substituted group as usedherein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I, —OH, protected hydroxy, —NO₂, —CN, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl,

—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH— heterocycloalkyl,

—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)—heterocycloalkyl,—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl,—NHCO₂-heterocycloalkyl, NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,NHC(O)NH-heterocycloalkyl,

NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl,

—S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl,—S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

It is understood that the aryls, heteroaryls, alkyls, and the like canbe further substituted.

The term “cancer” includes, but is not limited to, the followingcancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx;Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung:bronchogenic carcinoma (squamous cell or epidermoid, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma,lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas(ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel or small intestines (adenocarcinoma,lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel or large intestines(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma), colon, colon-rectum, colorectal, rectum; Genitourinarytract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,leukemia), bladder and urethra (squamous cell carcinoma, transitionalcell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma),testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma(hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma (serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia (acute and chronic), acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

The term “EGFR” herein refers to epidermal growth factor receptorkinase.

The term “HER” or “Her”, herein refers to human epidermal growth factorreceptor kinase.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient.

“Treat”, “treating” and “treatment” refer to a method of alleviating orabating a disease and/or its attendant symptoms.

As used herein, “preventing” or “prevent” describes reducing oreliminating the onset of the symptoms or complications of the disease,condition or disorder.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theapplication, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable include,but are not limited to, nontoxic acid addition salts are salts of anamino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate, and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present applicationwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic, and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates, and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentapplication which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present application. “Prodrug”, as used hereinmeans a compound which is convertible in vivo by metabolic means (e.g.,by hydrolysis) to afford any compound delineated by the formulae of theinstant application. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

This application also encompasses pharmaceutical compositionscontaining, and methods of treating disorders through administering,pharmaceutically acceptable prodrugs of compounds of the application.For example, compounds of the application having free amino, amido,hydroxy or carboxylic groups can be converted into prodrugs. Prodrugsinclude compounds wherein an amino acid residue, or a polypeptide chainof two or more (e.g., two, three or four) amino acid residues iscovalently joined through an amide or ester bond to a free amino,hydroxy or carboxylic acid group of compounds of the application. Theamino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities

Combinations of substituents and variables envisioned by thisapplication are only those that result in the formation of stablecompounds. The term “stable”, as used herein, refers to compounds whichpossess stability sufficient to allow manufacture and which maintainsthe integrity of the compound for a sufficient period of time to beuseful for the purposes detailed herein (e.g., therapeutic orprophylactic administration to a subject).

The application also provides for a pharmaceutical compositioncomprising a compound of the present disclosure, or a pharmaceuticallyacceptable ester, salt, or prodrug thereof, together with apharmaceutically acceptable carrier.

In another aspect, the application provides a kit comprising a compoundcapable of inhibiting EGFR activity selected from one or more compoundsof any of the formulae described herein, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, and instructions for use in treating cancer.

In another aspect, the application provides a method of synthesizing acompound of the present disclosure.

The synthesis of the compounds of the application can be found hereinand in the Examples below.

Another embodiment is a method of making a compound of any of theformulae herein using any one, or combination of, reactions delineatedherein. The method can include the use of one or more intermediates orchemical reagents delineated herein.

Another aspect is an isotopically labeled compound of any of theformulae delineated herein. Such compounds have one or more isotopeatoms which may or may not be radioactive (e.g., ³H, ²H, ¹⁴C, ¹³C, ¹⁸F,³⁵S, ³²P, ¹²⁵I, and ¹³¹I) introduced into the compound. Such compoundsare useful for drug metabolism studies and diagnostics, as well astherapeutic applications.

A compound of the application can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of the application can be prepared by reacting the free acidform of the compound with a pharmaceutically acceptable inorganic ororganic base.

Alternatively, the salt forms of the compounds of the application can beprepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compounds of the application canbe prepared from the corresponding base addition salt or acid additionsalt from, respectively. For example a compound of the application in anacid addition salt form can be converted to the corresponding free baseby treating with a suitable base (e.g., ammonium hydroxide solution,sodium hydroxide, and the like). A compound of the application in a baseaddition salt form can be converted to the corresponding free acid bytreating with a suitable acid (e.g., hydrochloric acid, etc.).

Prodrug derivatives of the compounds of the application can be preparedby methods known to those of ordinary skill in the art (e.g., forfurther details see Saulnier et al., (1994), Bioorganic and MedicinalChemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugscan be prepared by reacting a non-derivatized compound of theapplication with a suitable carbamylating agent (e.g.,1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or thelike).

Protected derivatives of the compounds of the application can be made bymeans known to those of ordinary skill in the art. A detaileddescription of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, “ProtectingGroups in Organic Chemistry”, 3rd edition, John Wiley and Sons, Inc.,1999.

Compounds of the present application can be conveniently prepared, orformed during the process of the application, as solvates (e.g.,hydrates). Hydrates of compounds of the present application can beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Acids and bases useful in the methods herein are known in the art. Acidcatalysts are any acidic chemical, which can be inorganic (e.g.,hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic(e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid,ytterbium triflate) in nature. Acids are useful in either catalytic orstoichiometric amounts to facilitate chemical reactions. Bases are anybasic chemical, which can be inorganic (e.g., sodium bicarbonate,potassium hydroxide) or organic (e.g., triethylamine, pyridine) innature. Bases are useful in either catalytic or stoichiometric amountsto facilitate chemical reactions.

In addition, some of the compounds of this application have one or moredouble bonds, or one or more asymmetric centers. Such compounds canoccur as racemates, racemic mixtures, single enantiomers, individualdiastereomers, diastereomeric mixtures, and cis- or trans- or E- orZ-double isomeric forms, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)-, or as(D)- or (L)- for amino acids. All such isomeric forms of these compoundsare expressly included in the present application. Optical isomers maybe prepared from their respective optically active precursors by theprocedures described herein, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Thecompounds of this application may also be represented in multipletautomeric forms, in such instances, the application expressly includesall tautomeric forms of the compounds described herein (e.g., alkylationof a ring system may result in alkylation at multiple sites, theapplication expressly includes all such reaction products). When thecompounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion. All such isomeric forms of suchcompounds are expressly included in the present application. All crystalforms of the compounds described herein are expressly included in thepresent application.

In the present specification, the structural formula of the compoundrepresents a certain isomer for convenience in some cases, but thepresent application includes all isomers, such as geometrical isomers,optical isomers based on an asymmetrical carbon, stereoisomers,tautomers, and the like. In addition, a crystal polymorphism may bepresent for the compounds represented by the formula. It is noted thatany crystal form, crystal form mixture, or anhydride or hydrate thereofis included in the scope of the present application. Furthermore,so-called metabolite which is produced by degradation of the presentcompound in vivo is included in the scope of the present application.

“Isomerism” means compounds that have identical molecular formulae butdiffer in the sequence of bonding of their atoms or in the arrangementof their atoms in space. Isomers that differ in the arrangement of theiratoms in space are termed “stereoisomers”. Stereoisomers that are notmirror images of one another are termed “diastereoisomers”, andstereoisomers that are non-superimposable mirror images of each otherare termed “enantiomers” or sometimes optical isomers. A mixturecontaining equal amounts of individual enantiomeric forms of oppositechirality is termed a “racemic mixture”.

A carbon atom bonded to four non-identical substituents is termed a“chiral center”.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

“Geometric isomer” means the diastereomers that owe their existence tohindered rotation about double bonds. These configurations aredifferentiated in their names by the prefixes cis and trans, or Z and E,which indicate that the groups are on the same or opposite side of thedouble bond in the molecule according to the Cahn-Ingold-Prelog rules.

Furthermore, the structures and other compounds discussed in thisapplication include all atropic isomers thereof. “Atropic isomers” are atype of stereoisomer in which the atoms of two isomers are arrangeddifferently in space. Atropic isomers owe their existence to arestricted rotation caused by hindrance of rotation of large groupsabout a central bond. Such atropic isomers typically exist as a mixture,however as a result of recent advances in chromatography techniques; ithas been possible to separate mixtures of two atropic isomers in selectcases.

“Tautomer” is one of two or more structural isomers that exist inequilibrium and is readily converted from one isomeric form to another.This conversion results in the formal migration of a hydrogen atomaccompanied by a switch of adjacent conjugated double bonds. Tautomersexist as a mixture of a tautomeric set in solution. In solid form,usually one tautomer predominates. In solutions where tautomerization ispossible, a chemical equilibrium of the tautomers will be reached. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent and pH. The concept of tautomers that areinterconvertable by tautomerizations is called tautomerism.

Of the various types of tautomerism that are possible, two are commonlyobserved. In keto-enol tautomerism a simultaneous shift of electrons anda hydrogen atom occurs. Ring-chain tautomerism arises as a result of thealdehyde group (—CHO) in a sugar chain molecule reacting with one of thehydroxy groups (—OH) in the same molecule to give it a cyclic(ring-shaped) form as exhibited by glucose. Common tautomeric pairs are:ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerismin heterocyclic rings (e.g., in nucleobases such as guanine, thymine andcytosine), amine-enamine and enamine-enamine.

The term “crystal polymorphs”, “polymorphs” or “crystal forms” meanscrystal structures in which a compound (or a salt or solvate thereof)can crystallize in different crystal packing arrangements, all of whichhave the same elemental composition. Different crystal forms usuallyhave different X-ray diffraction patterns, infrared spectral, meltingpoints, density hardness, crystal shape, optical and electricalproperties, stability and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Crystal polymorphs of the compounds can beprepared by crystallization under different conditions.

Additionally, the compounds of the present application, for example, thesalts of the compounds, can exist in either hydrated or unhydrated (theanhydrous) form or as solvates with other solvent molecules.Non-limiting examples of hydrates include monohydrates, dihydrates, etc.Non-limiting examples of solvates include ethanol solvates, acetonesolvates, etc.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate; and if the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one molecule of the substance inwhich the water retains its molecular state as H₂O.

The present application is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium, and isotopes of carbon include C-13 and C-14.

It is to be understood that the compounds of the present application maybe depicted as different tautomers. It should also be understood thatwhen compounds have tautomeric forms, all tautomeric forms are intendedto be included in the scope of the present application, and the namingof the compounds does not exclude any tautomer form.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent application. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this application may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The compounds of the application are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

Method of Synthesizing the Compounds

The compounds of the present application may be made by a variety ofmethods, including standard chemistry. The synthetic processes of theapplication can tolerate a wide variety of functional groups, thereforevarious substituted starting materials can be used. The processesgenerally provide the desired final compound at or near the end of theoverall process, although it may be desirable in certain instances tofurther convert the compound to a pharmaceutically acceptable salt,ester or prodrug thereof. Suitable synthetic routes are depicted in theScheme I below.

Compounds of the present application can be prepared in a variety ofways using commercially available starting materials, compounds known inthe literature, or from readily prepared intermediates, by employingstandard synthetic methods and procedures either known to those skilledin the art, or which will be apparent to the skilled artisan in light ofthe teachings herein. Standard synthetic methods and procedures for thepreparation of organic molecules and functional group transformationsand manipulations can be obtained from the relevant scientificliterature or from standard textbooks in the field. Although not limitedto any one or several sources, classic texts such as Smith, M. B.,March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 5^(th) edition, John Wiley & Sons: New York, 2001; andGreene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis,3^(rd) edition, John Wiley & Sons: New York, 1999, incorporated byreference herein, are useful and recognized reference textbooks oforganic synthesis known to those in the art. The following descriptionsof synthetic methods are designed to illustrate, but not to limit,general procedures for the preparation of compounds of the presentapplication.

The compounds of present application (e.g., a compound of Formula (I′))may be prepared by methods known in the art of organic synthesis as setforth in part by the following synthetic schemes. In the schemesdescribed below, it is well understood that protecting groups forsensitive or reactive groups are employed where necessary in accordancewith general principles or chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (T. W. Greene and P.G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition,Wiley, New York 1999). These groups are removed at a convenient stage ofthe compound synthesis using methods that are readily apparent to thoseskilled in the art. The selection processes, as well as the reactionconditions and order of their execution, shall be consistent with thepreparation of compounds of the present application (e.g., a compound ofFormula (I′)).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of the present application (e.g., a compound of Formula (I′)).Accordingly, the present application includes both possiblestereoisomers (unless specified in the synthesis) and includes not onlyracemic compounds but the individual enantiomers and/or diastereomers aswell. When a compound is desired as a single enantiomer or diastereomer,it may be obtained by stereospecific synthesis or by resolution of thefinal product or any convenient intermediate. Resolution of the finalproduct, an intermediate, or a starting material may be affected by anysuitable method known in the art. See, for example, “Stereochemistry ofOrganic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

All the abbreviations used in this application are found in “ProtectiveGroups in Organic Synthesis” by John Wiley & Sons, Inc, or the MERCKINDEX by MERCK & Co., Inc, or other chemistry books or chemicalscatalogs by chemicals vendor such as Aldrich, or according to usage knowin the art.

Preparation of Compounds

The compounds of the present application can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present application can be synthesizedusing the methods described below, together with synthetic methods knownin the art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent application can be synthesized by following the steps outlinedin General Scheme 1 which comprise different sequences of assemblingintermediates Ia, Ib, Ic, Id, Ie, If, Ig, and Ih. Starting materials areeither commercially available or made by known procedures in thereported literature or as illustrated.

wherein R₁-R₃, R₆, R₇, R₁₀, R₁₁, Z₁, Z₂, and Z₃ are defined as inFormula (I′).

The general way of preparing target molecules I′ by using intermediatesIa, Ib, Ic, Id, Ie, Ih, Ii, Ig, and Ih is outlined in General Scheme 1.Acylation of Ia with Ib using a base, i.e., triethylamine (Et₃N), insolvent, i.e., dioxane, at elevated temperatures provides intermediateIc. Intermediate Id is then prepared by alkylation of Ic withdichloropyrimidine in the presence of a base, i.e., sodium hydride(NaH), and in a solvent, i.e., dimethylformamide (DMF). Reduction of thenitro group in the presence of a metal salt, i.e., stannous chloridedihydrate (SnCl₂.2H₂O) or chromium (II) chloride (CrCl₂), and an acid,i.e., hydrochloric acid (HCl) in solvent, i.e., ethyl acetate providesintermediate Ie. Acylation of Ie with acyl chloride If using a base,i.e., sodium bicarbonate (NaHCO₃) or potassium bicarbonate (KHCO₃), insolvent, i.e., tetrahydrofuran/water (THF/H₂O) provides Ig. Amination ofIg with arylamine Ih using an acid, i.e., trifluoroacetic acid (TFA) ina solvent, i.e., 2-butanol, provides the desired compound of Formula(I′).

A mixture of enantiomers, diastereomers, cis/trans isomers resultingfrom the process described above can be separated into their singlecomponents by chiral salt technique, chromatography using normal phase,reverse phase or chiral column, depending on the nature of theseparation.

It should be understood that in the description and formula shown above,the various groups R₁, R₂, R₆, R₁₀, R₁₁, and n and other variables areas defined above, except where otherwise indicated. Furthermore, forsynthetic purposes, the compounds of General Scheme 1 are mererepresentatives with elected radicals to illustrate the generalsynthetic methodology of the compounds of Formula (I′) as definedherein.

Biological Assays Cell Proliferation Assays and Growth Assays of EGFRExon 20 Insertion Mutation Ba/F3 Cells

EGFR mutations are introduced via site directed mutagenesis into fulllength EGFR (i.e., exon 20 insertions including, but not limited toD770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH,H773dupH, H773_V774insNPH, and P772_H773insPNP; or HER2 insertion, suchas insYVMA). All constructs are confirmed by DNA sequencing. Theconstructs are shuttled into a retroviral vector and Ba/F3 cells areinfected with the retroviral constructs. Stable clones are obtained byselection in puromycin and growth in IL-3 free media.

Murine Ba/F3 cells are engineered to express mutant and wild type EGFRor HER2 protein and used to perform single drug screens. Cell viabilityis assessed after compound exposure using a colorimetric cellproliferation MTS assay. Non-small cell lung cancer (NSCLC) cell linesor Ba/F3 cells harboring specific mutations (i.e., exon 20 insertion)are exposed to treatment and the number of cells used per experiment isdetermined empirically. Proliferation assays are performed at a range (0to 10 μM) of inhibitor concentrations and an EC₅₀ is calculated. Allexperimental points are set up in wells and all experiments wererepeated at least three times. The curves are fitted using a non-linearregression model with a sigmoidal dose response.

Antibodies and Western Blotting

Cells are and lysed in buffer. Western blot analyses are conducted afterseparation by SDS/PAGE electrophoresis and transfer to polyvinylidenedifluoride-P membrane. Immunoblotting is then performed. Antibodybinding is detected using an enhanced chemiluminescence system.

Generation of Mouse Cohorts and Treatment with Compounds of Formula (I)

EGFR-exon 20 insertion inducible mice are generated and characterized.Exon 20 mutations are introduced via site directed mutagenesis into fulllength EGFR. All constructs are confirmed by DNA sequencing and theconstructs are shuttled into a retroviral vector. Transgenic mice arethen generated by injection of the construct into FVB/N fertilized eggs.Progeny are genotyped through PCR exactly the same as reported. Foundersare crossed with CCSP-rtTA mice and inducible bitransgenic mice withhigh and inducible expression of the mutant hEGFR transgene areidentified and expanded for subsequent analyses and experiments.

Cohorts of EGFR-exon 20 insertion/CCSP-rtTA are put on doxycycline dietat 5 weeks of age to induce the expression of mutant EGFR. These miceundergo MRI after 6 to 8 weeks of doxycycline diet to document andquantify the lung cancer burden before being assigned to varioustreatment study cohorts. Mice are then treated either with vehicle or acompound disclosed herein. After 2 weeks of treatment, the mice undergoa second round of MRI to document their response to the treatment andchanges in tumor volume are calculated.

MRI Scanning and Tumor Volume Measurement

Mice are anesthetized with isoflurane in an oxygen/air mixture. Therespiratory and cardiac rates of anesthetized mice are monitored. Theanimals are then imaged with a rapid acquisition with relaxationenhancement (RARE) sequence and with a gradient echo fast imaging (GEFI)sequence

Immunohistochemical Analyses

Immunohistochemistry is performed on formal fixed paraffin embeddedtumor sections. Total EGFR and phospho-EGFR antibodies are used (i.e.,Y1068 and Ki67). Apoptosis is measured by counting nuclear bodies in H&E(Hematoxylin and eosin) stained sections and by a terminaldeoxynucleotidyl-transferase mediated dUTP-biotin nick end labeling(TUNEL) assay.

Pharmacokinetic Analyses

Dose administration: All mice are weighed before dose administration andrandomized. For intravenous administration, a freshly prepared solutionof a compound of the present disclosure is administered via tail vein ata slow and steady rate. For oral administration, freshly preparedsuspension of a compound of the present disclosure is administered bystomach intubation using an oral feeding needle.

Blood samples are collected from the saphenous vein of each mouse atregular intervals. During each sampling point, blood samples arecollected in labeled microtubes containing K2EDTA as an anticoagulant.Samples are centrifuged and the recovered quantity of plasma from eachsample is transferred to labeled micro-tubes. The plasma samples arethen stored at a low temperature until bioanalysis.

Bioanalytical method for the determination of a compound of the presentdisclosure in mouse plasma is developed using LC-MS/MS equipment. Themethod is partially validated prior to sample analysis.

The pharmacokinetic parameters of a compound of the present disclosuresuch as T_(max), C_(max), AUC, CL, V_(d), T_(1/2), and bioavailabilityin mouse plasma are determined from the concentration-time data usingnon-compartmental analysis.

Serum Creatinine and White Blood Cell Count Analyses

Blood is collected from vehicle and compound of Formula (I′) treatedmice into appropriate tubes and analyzed.

Methods of the Application

In another aspect, the application provides a method of inhibiting akinase, comprising contacting the kinase with a compound of the presentdisclosure, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof. In some embodiments, thekinase comprises an exon 20 insertion. In other embodiments, the exoninsertion is selected from 70delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, or H773dupH. In further embodiments, the kinasecomprises a HER2 insertion. In other embodiments, the HER2 insertion isinsYVMA. In other embodiments, the kinase comprises a cysteine residue.In other embodiments, the kinase comprises a cysteine residue. Infurther embodiments, the cysteine residue is located in or near theposition equivalent to Cys 797 in EGFR, including such position in Jak3,Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec, and Txk.

In another aspect, the application provides a method of inhibiting akinase, the method comprising administering to a subject in need thereofan effective amount of a compound of the present disclosure, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. In some embodiments, the EGFR is aHer-kinase.

In still another aspect, the application provides a method of inhibitingepidermal growth factor receptor (EGFR), the method comprisingadministering to a subject in need thereof an effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the application provides a method of treating orpreventing a disease, the method comprising administering to a subjectin need thereof an effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof. In some embodiments, thedisease is mediated by a kinase. In further embodiments, the kinasecomprises an exon 20 insertion. In other embodiments, the exon insertionis selected from 70delinsGY, D770_N771insSVD, V769_D770insASV,Y764_V765insHH, or H773dupH. In further embodiments, the kinasecomprises a HER2 insertion. In other embodiments, the HER2 insertion isinsYVMA. In other embodiments, the kinase comprises a cysteine residue.In still a further embodiment, the cysteine residue is located in ornear the position equivalent to Cys 797 in EGFR, including suchpositions in Jak3, Blk, Bmx, Btk, HER2 (ErbB2), HER4 (ErbB4), Itk, Tec,and Txk.

In other embodiments, the disease is mediated by EGFR (e.g., EGFR playsa role in the initiation or development of the disease). In furtherembodiments, the EGFR is a Her-kinase. In further embodiments, theHer-kinase is HER1, HER2, or HER4. In further embodiments, theHer-kinase is HER2.

In certain embodiments, the disease is cancer or a proliferationdisease.

In further embodiments, the disease is lung cancer, colon cancer, breastcancer, prostate cancer, liver cancer, pancreas cancer, brain cancer,kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma,hepatocellular carcinoma, papillary renal carcinoma, head and necksquamous cell carcinoma, leukemias, lymphomas, myelomas, or solidtumors.

In other embodiments, the disease is inflammation, arthritis, rheumatoidarthritis, spondyiarthropathies, gouty arthritis, osteoarthritis,juvenile arthritis, and other arthritic conditions, systemic lupuserthematosus (SLE), skin-related conditions, psoriasis, eczema, burns,dermatitis, neuroinflammation, allergy, pain, neuropathic pain, fever,pulmonary disorders, lung inflammation, adult respiratory distresssyndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonaryinflammatory disease, and chronic obstructive pulmonary disease (COPD),cardiovascular disease, arteriosclerosis, myocardial infarction(including post-myocardial infarction indications), thrombosis,congestive heart failure, cardiac reperfusion injury, as well ascomplications associated with hypertension and/or heart failure such asvascular organ damage, restenosis, cardiomyopathy, stroke includingischemic and hemorrhagic stroke, reperfusion injury, renal reperfusioninjury, ischemia including stroke and brain ischemia, and ischemiaresulting from cardiac/coronary bypass, neurodegenerative disorders,liver disease and nephritis, gastrointestinal conditions, inflammatorybowel disease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, ulcerative diseases, gastric ulcers, viral andbacterial infections, sepsis, septic shock, gram negative sepsis,malaria, meningitis, HIV infection, opportunistic infections, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex),pneumonia, herpes virus, myalgias due to infection, influenza,autoimmune disease, graft vs. host reaction and allograft rejections,treatment of bone resorption diseases, osteoporosis, multiple sclerosis,cancer, leukemia, lymphoma, colorectal cancer, brain cancer, bonecancer, epithelial call-derived neoplasia (epithelial carcinoma), basalcell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer,mouth cancer, esophageal cancer, small bowel cancer, stomach cancer,colon cancer, liver cancer, bladder cancer, pancreas cancer, ovariancancer, cervical cancer, lung cancer, breast cancer, skin cancer,squamus cell and/or basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that affect epithelial cellsthroughout the body, chronic myelogenous leukemia (CML), acute myeloidleukemia (AML) and acute promyelocytic leukemia (APL), angiogenesisincluding neoplasia, metastasis, central nervous system disorders,central nervous system disorders having an inflammatory or apoptoticcomponent, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis, spinal cord injury, andperipheral neuropathy, or B-Cell Lymphoma.

In further embodiments, the disease is inflammation, arthritis,rheumatoid arthritis, spondylarthropathies, gouty arthritis,osteoarthritis, juvenile arthritis, and other arthritic conditions,systemic lupus erthematosus (SLE), skin-related conditions, psoriasis,eczema, dermatitis, pain, pulmonary disorders, lung inflammation, adultrespiratory distress syndrome, pulmonary sarcoisosis, asthma, chronicpulmonary inflammatory disease, and chronic obstructive pulmonarydisease (COPD), cardiovascular disease, arteriosclerosis, myocardialinfarction (including post-myocardial infarction indications),congestive heart failure, cardiac reperfusion injury, inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome, leukemiaor lymphoma.

In another aspect, the application provides a method of treating akinase mediated disorder, the method comprising administering to asubject in need thereof an effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof. In some embodiments, thecompound is an inhibitor of HER1, HER2, or HER4. In other embodiments,the compound is an inhibitor of HER2. In other embodiments, the subjectis administered an additional therapeutic agent. In other embodiments,the compound and the additional therapeutic agent are administeredsimultaneously or sequentially.

In other embodiments, the disease is cancer. In further embodiments, thecancer is lung cancer, colon cancer, breast cancer, prostate cancer,liver cancer, pancreas cancer, brain cancer, kidney cancer, ovariancancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breastcancer, pancreatic cancer, glioma, glioblastoma, hepatocellularcarcinoma, papillary renal carcinoma, head and neck squamous cellcarcinoma, leukemias, lymphomas, myelomas, or solid tumors.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprise activated EGFR,comprising administering to a subject in need thereof an effectiveamount of a compound of the present disclosure, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In certain embodiments, the EGFR activation is selected from mutation ofEGFR, amplification of EGFR, expression of EGFR, and ligand mediatedactivation of EGFR.

In further embodiment, the mutation of EGFR is located at G719S, G719C,G719A, L858R, L861Q, an exon 19 deletion mutation, HER2 insertion (i.e.,insYVMA), or an exon 20 insertion mutation (i.e., 770delinsGY,D770_N771insSVD, V769_D770insASV, Y764_V765insHH, or H773dupH).

Another aspect of the application provides a method of treating orpreventing cancer in a subject, wherein the subject is identified asbeing in need of EGFR inhibition for the treatment of cancer, comprisingadministering to the subject an effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In certain embodiments, the subject is identified as being in need ofEGFR inhibition is resistant to a known EGFR inhibitor, including butnot limited to, gefitinib or erlotinib. In certain embodiments, adiagnostic test is performed to determine if the subject has anactivating mutation in EGFR. In certain embodiments, a diagnostic testis performed to determine if the subject has an EGFR harboring anactivating and a drug resistance mutation. Activating mutations comprisewithout limitation L858R, G719S, G719C, G719A, L718Q, L861Q, a deletionin exon 19, a HER2 insertion (i.e., insYVMA) and/or an insertion in exon20 (i.e., 770delinsGY, D770_N771insSVD, V769_D770insASV, Y764_V765insHH,or H773dupH). Drug resistant EGFR mutants can have without limitation adrug resistance mutation comprising T790M, T854A, L718Q, or D761Y. Thediagnostic test can comprise sequencing, pyrosequencing, PCR, RT-PCR, orsimilar analysis techniques known to those of skill in the art that candetect nucleotide sequences.

In another aspect, the application provides a method of treating orpreventing cancer, wherein the cancer cell comprises an activated ERBB2,comprising administering to a subject in need thereof an effectiveamount of a compound of the present disclosure, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. In certain embodiments, the ERBB2 activation is selected frommutation of ERBB2, expression of ERBB2 and amplification of ERBB2. Infurther embodiments, the mutation is a mutation in exon 20 of ERBB2.

In further embodiments, the cancer is lung cancer, colon cancer, breastcancer, prostate cancer, liver cancer, pancreas cancer, brain cancer,kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer,gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma,hepatocellular carcinoma, papillary renal carcinoma, head and necksquamous cell carcinoma, leukemias, lymphomas, myelomas, or solidtumors.

In still another aspect, the application provides a method of treatingcancer in a subject, wherein the subject is identified as being in needof ERBB2 inhibition for the treatment of cancer, comprisingadministering to the subject in need thereof an effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the application provides a method of preventingresistance to a known EGFR inhibitor, including but not limited to,gefitinib or erlotinib in a disease, comprising administering to asubject in need thereof an effective amount of a compound of the presentdisclosure, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

In certain embodiments, the disease is cancer. In further embodiments,the cancer is lung cancer, colon cancer, breast cancer, prostate cancer,liver cancer, pancreas cancer, brain cancer, kidney cancer, ovariancancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breastcancer, pancreatic cancer, glioma, glioblastoma, hepatocellularcarcinoma, papillary renal carcinoma, head and neck squamous cellcarcinoma, leukemias, lymphomas, myelomas, or solid tumors.

In certain embodiments, the application provides a method of treatingany of the disorders described herein, wherein the subject is a human.In certain embodiments, the application provides a method of preventingany of the disorders described herein, wherein the subject is a human.

In another aspect, the application provides a compound of the presentdisclosure, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in the manufactureof a medicament for treating or preventing a disease in which EGFR playsa role.

In still another aspect, the application provides the use of a compoundof the present disclosure, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in thetreatment or prevention of a disease in which EGFR plays a role.

As inhibitors of Her kinases, the compounds and compositions of thisapplication are particularly useful for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease, condition, or disorder. In one aspect, thepresent application provides a method for treating or lessening theseverity of a disease, condition, or disorder where a protein kinase isimplicated in the disease state. In another aspect, the presentapplication provides a method for treating or lessening the severity ofa kinase disease, condition, or disorder where inhibition of enzymaticactivity is implicated in the treatment of the disease. In anotheraspect, this application provides a method for treating or lessening theseverity of a disease, condition, or disorder with compounds thatinhibit enzymatic activity by binding to the protein kinase. Anotheraspect provides a method for treating or lessening the severity of akinase disease, condition, or disorder by inhibiting enzymatic activityof the kinase with a protein kinase inhibitor.

In some embodiments, said method is used to treat or prevent a conditionselected from autoimmune diseases, inflammatory diseases, proliferativeand hyperproliferative diseases, immunologically-mediated diseases, bonediseases, metabolic diseases, neurological and neurodegenerativediseases, cardiovascular diseases, hormone related diseases, allergies,asthma, and Alzheimer's disease. In other embodiments, said condition isselected from a proliferative disorder and a neurodegenerative disorder.

One aspect of this application provides compounds that are useful forthe treatment of diseases, disorders, and conditions characterized byexcessive or abnormal cell proliferation. Such diseases include, but arenot limited to, a proliferative or hyperproliferative disease, and aneurodegenerative disease. Examples of proliferative andhyperproliferative diseases include, without limitation, cancer. Theterm “cancer” includes, but is not limited to, the following cancers:breast; ovary; cervix; prostate; testis, genitourinary tract; esophagus;larynx, glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma;lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma; bone; colon; colorectal; adenoma; pancreas,adenocarcinoma; thyroid, follicular carcinoma, undifferentiatedcarcinoma, papillary carcinoma; seminoma; melanoma; sarcoma; bladdercarcinoma; liver carcinoma and biliary passages; kidney carcinoma;myeloid disorders; lymphoid disorders, Hodgkin's, hairy cells; buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx; small intestine;colonrectum, large intestine, rectum, brain and central nervous system;chronic myeloid leukemia (CML), and leukemia. The term “cancer”includes, but is not limited to, the following cancers: myeloma,lymphoma, or a cancer selected from gastric, renal, or and the followingcancers: head and neck, oropharangeal, non-small cell lung cancer(NSCLC), endometrial, hepatocarcinoma, Non-Hodgkins lymphoma, andpulmonary.

The term “cancer” refers to any cancer caused by the proliferation ofmalignant neoplastic cells, such as tumors, neoplasms, carcinomas,sarcomas, leukemias, lymphomas and the like. For example, cancersinclude, but are not limited to, mesothelioma, leukemias and lymphomassuch as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral Tcelllymphomas, lymphomas associated with human T-cell lymphotrophic virus(HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma,acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronicmyelogenous leukemia, acute myelogenous leukemia, lymphomas, andmultiple myeloma, non-Hodgkin lymphoma, acute lymphatic leukemia (ALL),chronic lymphatic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma,adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronicmyeloid leukemia (CML), or hepatocellular carcinoma. Further examplesinclude myelodisplastic syndrome, childhood solid tumors such as braintumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, andsoft-tissue sarcomas, common solid tumors of adults such as head andneck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal),genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian,testicular), lung cancer (e.g., small-cell and non-small cell), breastcancer, pancreatic cancer, melanoma and other skin cancers, stomachcancer, brain tumors, tumors related to Gorlin's syndrome (e.g.,medulloblastoma, meningioma, etc.), and liver cancer. Additionalexemplary forms of cancer which may be treated by the subject compoundsinclude, but are not limited to, cancer of skeletal or smooth muscle,stomach cancer, cancer of the small intestine, rectum carcinoma, cancerof the salivary gland, endometrial cancer, adrenal cancer, anal cancer,rectal cancer, parathyroid cancer, and pituitary cancer.

Additional cancers that the compounds described herein may be useful inpreventing, treating and studying are, for example, colon carcinoma,familiary adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer, or melanoma. Further, cancers include, but are notlimited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma,tongue carcinoma, salivary gland carcinoma, gastric carcinoma,adenocarcinoma, thyroid cancer (medullary and papillary thyroidcarcinoma), renal carcinoma, kidney parenchyma carcinoma, cervixcarcinoma, uterine corpus carcinoma, endometrium carcinoma, chorioncarcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumorssuch as glioblastoma, astrocytoma, meningioma, medulloblastoma andperipheral neuroectodermal tumors, gall bladder carcinoma, bronchialcarcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma,choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma,osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma,Ewing sarcoma, and plasmocytoma. In one aspect of the application, thepresent application provides for the use of one or more compounds of theapplication in the manufacture of a medicament for the treatment ofcancer, including without limitation the various types of cancerdisclosed herein.

In some embodiments, the compounds of this application are useful fortreating cancer, such as colorectal, thyroid, breast, and lung cancer;and myeloproliferative disorders, such as polycythemia vera,thrombocythemia, myeloid metaplasia with myelofibrosis, chronicmyelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilicsyndrome, juvenile myelomonocytic leukemia, and systemic mast celldisease. In some embodiments, the compounds of this application areuseful for treating hematopoietic disorders, in particular,acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML),acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

This application further embraces the treatment or prevention of cellproliferative disorders such as hyperplasias, dysplasias, andpre-cancerous lesions. Dysplasia is the earliest form of pre-cancerouslesion recognizable in a biopsy by a pathologist. The subject compoundsmay be administered for the purpose of preventing said hyperplasias,dysplasias or pre-cancerous lesions from continuing to expand or frombecoming cancerous. Examples of pre-cancerous lesions may occur in skin,esophageal tissue, breast and cervical intra-epithelial tissue.

Examples of neurodegenerative diseases include, without limitation,Adrenoleukodystrophy (ALD), Alexander's disease, Alper's disease,Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig'sDisease), Ataxia telangiectasia, Batten disease (also known asSpielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiformencephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasaldegeneration, Creutzfeldt-Jakob disease, Familial fatal insomnia,Frontotemporal lobar degeneration, Huntington's disease, HIV-associateddementia, Kennedy's disease, Krabbe's disease, Lewy body dementia,Neuroborreliosis, Machado-Joseph disease (Spinocerebellar ataxia type3), Multiple System Atrophy, Multiple sclerosis, Narcolepsy, NiemannPick disease, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick'sdisease, Primary lateral sclerosis, Prion diseases, ProgressiveSupranuclear Palsy, Refsum's disease, Sandhoff disease, Schilder'sdisease, Subacute combined degeneration of spinal cord secondary toPernicious Anaemia, Spielmeyer-Vogt-Sjogren-Batten disease (also knownas Batten disease), Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, Tabes dorsalis, and Toxic encephalopathy.

Another aspect of this application provides a method for the treatmentor lessening the severity of a disease selected from a proliferative orhyperproliterative disease, or a neurodegenerative disease, comprisingadministering an effective amount of a compound, or a pharmaceuticallyacceptable composition comprising a compound, to a subject in needthereof.

As inhibitors of Her kinases, the compounds and compositions of thisapplication are also useful in biological samples. One aspect of theapplication relates to inhibiting protein kinase activity in abiological sample, which method comprises contacting said biologicalsample with a compound of the application or a composition comprisingsaid compound. The term “biological sample”, as used herein, means an invitro or an ex vivo sample, including, without limitation, cell culturesor extracts thereof; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof. Inhibition of protein kinaseactivity in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ-transplantation, andbiological specimen storage.

Another aspect of this application relates to the study of Her kinasesin biological and pathological phenomena; the study of intracellularsignal transduction pathways mediated by such protein kinases; and thecomparative evaluation of new protein kinase inhibitors. Examples ofsuch uses include, but are not limited to, biological assays such asenzyme assays and cell-based assays.

The activity of the compounds as Her kinase inhibitors may be assayed invitro, in vivo, or in a cell line. In vitro assays include assays thatdetermine inhibition of either the kinase activity or ATPase activity ofthe activated kinase. Alternate in vitro assays quantitate the abilityof the inhibitor to bind to the protein kinase and may be measuredeither by radio labelling the inhibitor prior to binding, isolating theinhibitor/kinase complex and determining the amount of radio labelbound, or by running a competition experiment where new inhibitors areincubated with the kinase bound to known radioligands. Detailedconditions for assaying a compound utilized in this application as aninhibitor of various kinases are set forth in the Examples below.

In accordance with the foregoing, the present application furtherprovides a method for preventing or treating any of the diseases ordisorders described above in a subject in need of such treatment, whichmethod comprises administering to said subject a therapeuticallyeffective amount of a compound of the application, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof. For any of the above uses, the required dosage will varydepending on the mode of administration, the particular condition to betreated and the effect desired.

Pharmaceutical Compositions

In another aspect, the application provides a pharmaceutical compositioncomprising a compound of Formula (I′), or a pharmaceutically acceptableester, salt, or prodrug thereof, together with a pharmaceuticallyacceptable carrier.

Compounds of the application can be administered as pharmaceuticalcompositions by any conventional route, in particular enterally, e.g.,orally, e.g., in the form of tablets or capsules, or parenterally, e.g.,in the form of injectable solutions or suspensions, topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form. Pharmaceutical compositions comprising a compound ofthe present application in free form or in a pharmaceutically acceptablesalt form in association with at least one pharmaceutically acceptablecarrier or diluent can be manufactured in a conventional manner bymixing, granulating or coating methods. For example, oral compositionscan be tablets or gelatin capsules comprising the active ingredienttogether with a) diluents, e.g., lactose, dextrose, sucrose, mannitol,sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum,stearic acid, its magnesium or calcium salt and/or polyethyleneglycol;for tablets also c) binders, e.g., magnesium aluminum silicate, starchpaste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose and or polyvinylpyrrolidone; if desired d)disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or e) absorbents, colorants, flavors andsweeteners. Injectable compositions can be aqueous isotonic solutions orsuspensions, and suppositories can be prepared from fatty emulsions orsuspensions. The compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Suitable formulations for transdermal applicationsinclude an effective amount of a compound of the present applicationwith a carrier. A carrier can include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.Matrix transdermal formulations may also be used. Suitable formulationsfor topical application, e.g., to the skin and eyes, are preferablyaqueous solutions, ointments, creams or gels well-known in the art. Suchmay contain solubilizers, stabilizers, tonicity enhancing agents,buffers and preservatives.

Compounds of the application can be administered in therapeuticallyeffective amounts in a combinational therapy with one or moretherapeutic agents (pharmaceutical combinations) or modalities, e.g.,non-drug therapies. For example, synergistic effects can occur withother anti-proliferative, anti-cancer, immunomodulatory oranti-inflammatory substances. Where the compounds of the application areadministered in conjunction with other therapies, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the condition beingtreated and so forth.

Combination therapy includes the administration of the subject compoundsin further combination with other biologically active ingredients (suchas, but not limited to, a second and different antineoplastic agent) andnon-drug therapies (such as, but not limited to, surgery or radiationtreatment). For instance, the compounds of the application can be usedin combination with other pharmaceutically active compounds, preferablycompounds that are able to enhance the effect of the compounds of theapplication. The compounds of the application can be administeredsimultaneously (as a single preparation or separate preparation) orsequentially to the other drug therapy or treatment modality. Ingeneral, a combination therapy envisions administration of two or moredrugs during a single cycle or course of therapy.

In one aspect of the application, the compounds may be administered incombination with one or more separate agents that modulate proteinkinases involved in various disease states. Examples of such kinases mayinclude, but are not limited to: serine/threonine specific kinases,receptor tyrosine specific kinases and non-receptor tyrosine specifickinases. Serine/threonine kinases include mitogen activated proteinkinases (MAPK), meiosis specific kinase (MEK), RAF and aurora kinase.Examples of receptor kinase families include epidermal growth factorreceptor (EGFR) (e.g. HER2/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4,Xmrk, DER, Let23); fibroblast growth factor (FGF) receptor (e.g. FGF-R1,GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocytegrowth/scatter factor receptor (HGFR) (e.g., MET, RON, SEA, SEX);insulin receptor (e.g. IGFI-R); Eph (e.g. CEK5, CEK8, EBK, ECK, EEK,EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Ax1 (e.g., Mer/Nyk,Rse); RET; and platelet-derived growth factor receptor (PDGFR) (e.g.,PDGF.alpha.-R, PDG.beta.-R, CSFI-RIFMS, SCF-R/C-KIT, VEGF-R/FLT, NEK/FLK1, FLT3/FLK2/STK-1). Non-receptor tyrosine kinase families include, butare not limited to, BCR-ABL (e.g., p43.sup.abl, ARG); BTK (e.g. TTK/EMT,TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the application, the subject compounds may beadministered in combination with one or more agents that modulatenon-kinase biological targets or processes. Such targets include histonedeacetylases (HDAC), DNA methyltransferase (DNMT), heat shock proteins(e.g. HSP90), and proteosomes.

In a preferred embodiment, subject compounds may be combined withantineoplastic agents (e.g., small molecules, monoclonal antibodies,antisense RNA, and fusion proteins) that inhibit one or more biologicaltargets such as Zolinza, Tarceva, Iressa, Tykerb, Gleevec, Sutent,Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak,Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322,Obatodax, ABT737 and AEE788. Such combinations may enhance therapeuticefficacy over efficacy achieved by any of the agents alone and mayprevent or delay the appearance of resistant mutational variants.

In certain preferred embodiments, the compounds of the application areadministered in combination with a chemotherapeutic agent.Chemotherapeutic agents encompass a wide range of therapeutic treatmentsin the field of oncology. These agents are administered at variousstages of the disease for the purposes of shrinking tumors, destroyingremaining cancer cells left over after surgery, inducing remission,maintaining remission and/or alleviating symptoms relating to the canceror its treatment. Examples of such agents include, but are not limitedto, alkylating agents such as mustard gas derivatives (Mechlorethamine,cyclophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimines(thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazinesand Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide),Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide andmetal salts (Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloidssuch as Podophyllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxeland Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine andVinorelbine), and Camptothecan analogs (lrinotecan and Topotecan);anti-tumor antibiotics such as Chromomycins (Dactinomycin andPlicamycin), Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin,Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibioticssuch as Mitomycin, Actinomycin and Bleomycin; anti-metabolites such asfolic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed,Aminopterin), pyrimidine antagonists (5-Fluorouracil, Floxuridine,Cytarabine, Capecitabine, and Gemcitabine), purine antagonists(6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors(Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine,Nelarabine and Pentostatin); topoisomerase inhibitors such astopoisomerase I inhibitors (Ironotecan, topotecan) and topoisomerase IIinhibitors (Amsacrine, etoposide, etoposide phosphate, teniposide);monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab,Trastuzumab, Ibritumomab Tioxetan, Cetuximab, Panitumumab, Tositumomab,Bevacizumab); and miscellaneous anti-neoplastics such as ribonucleotidereductase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor(Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubuleagents (Estramustine); and retinoids (Bexarotene, Isotretinoin,Tretinoin (ATRA).

In certain preferred embodiments, the compounds of the application areadministered in combination with a chemoprotective agent.Chemoprotective agents act to protect the body or minimize the sideeffects of chemotherapy. Examples of such agents include, but are notlimited to, amfostine, mesna, and dexrazoxane.

In one aspect of the application, the subject compounds are administeredin combination with radiation therapy. Radiation is commonly deliveredinternally (implantation of radioactive material near cancer site) orexternally from a machine that employs photon (x-ray or gamma-ray) orparticle radiation. Where the combination therapy further comprisesradiation treatment, the radiation treatment may be conducted at anysuitable time so long as a beneficial effect from the co-action of thecombination of the therapeutic agents and radiation treatment isachieved. For example, in appropriate cases, the beneficial effect isstill achieved when the radiation treatment is temporally removed fromthe administration of the therapeutic agents, perhaps by days or evenweeks.

It will be appreciated that compounds of the application can be used incombination with an immunotherapeutic agent. One form of immunotherapyis the generation of an active systemic tumor-specific immune responseof host origin by administering a vaccine composition at a site distantfrom the tumor. Various types of vaccines have been proposed, includingisolated tumor-antigen vaccines and anti-idiotype vaccines. Anotherapproach is to use tumor cells from the subject to be treated, or aderivative of such cells (reviewed by Schirrmacher et al. (1995) J.Cancer Res. Clin. Oncol. 121:487). In U.S. Pat. No. 5,484,596, Hanna Jr.et al. claim a method for treating a resectable carcinoma to preventrecurrence or metastases, comprising surgically removing the tumor,dispersing the cells with collagenase, irradiating the cells, andvaccinating the patient with at least three consecutive doses of about10⁷ cells.

It will be appreciated that the compounds of the application mayadvantageously be used in conjunction with one or more adjunctivetherapeutic agents. Examples of suitable agents for adjunctive therapyinclude a 5HT₁ agonist, such as a triptan (e.g., sumatriptan ornaratriptan); an adenosine A1 agonist; an EP ligand; an NMDA modulator,such as a glycine antagonist; a sodium channel blocker (e.g.lamotrigine); a substance P antagonist (e.g., an NK₁ antagonist); acannabinoid; acetaminophen or phenacetin; a 5-lipoxygenase inhibitor; aleukotriene receptor antagonist; a DMARD (e.g., methotrexate);gabapentin and related compounds; a tricyclic antidepressant (e.g.,amitryptilline); a neurone stabilising antiepileptic drug; amono-aminergic uptake inhibitor (e.g., venlafaxine); a matrixmetalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor,such as an iNOS or an nNOS inhibitor; an inhibitor of the release, oraction, of tumor necrosis factor a; an antibody therapy, such as amonoclonal antibody therapy; an antiviral agent, such as a nucleosideinhibitor (e.g., lamivudine) or an immune system modulator (e.g.,interferon); an opioid analgesic; a local anesthetic; a stimulant,including caffeine; an H₂-antagonist (e.g., ranitidine); a proton pumpinhibitor (e.g., omeprazole); an antacid (e.g., aluminum or magnesiumhydroxide; an antiflatulent (e.g. simethicone); a decongestant (e.g.phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline,epinephrine, naphazoline, xylometazoline, propylhexedrine, orlevo-desoxyephedrine); an antitussive (e.g., codeine, hydrocodone,carmiphen, carbetapentane, or dextramethorphan); a diuretic; or asedating or non-sedating antihistamine.

The pharmaceutical compositions of the present application comprise atherapeutically effective amount of a compound of the presentapplication formulated together with one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticallyacceptable carrier” means a non-toxic, inert solid, semi-solid or liquidfiller, diluent, encapsulating material or formulation auxiliary of anytype. The pharmaceutical compositions of this application can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisapplication with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis application include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this application.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this application, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisapplication, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present application,disorders are treated or prevented in a subject, such as a human orother animal, by administering to the subject a therapeuticallyeffective amount of a compound of the application, in such amounts andfor such time as is necessary to achieve the desired result. The term“therapeutically effective amount” of a compound of the application, asused herein, means a sufficient amount of the compound so as to decreasethe symptoms of a disorder in a subject. As is well understood in themedical arts a therapeutically effective amount of a compound of thisapplication will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

In general, compounds of the application will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Ingeneral, satisfactory results are indicated to be obtained systemicallyat daily dosages of from about 0.03 to 2.5 mg/kg per body weight. Anindicated daily dosage in the larger mammal, e.g., humans, is in therange from about 0.5 mg to about 100 mg, conveniently administered,e.g., in divided doses up to four times a day or in retard form.Suitable unit dosage forms for oral administration comprise from ca. 1to 50 mg active ingredient.

In certain embodiments, a therapeutic amount or dose of the compounds ofthe present application may range from about 0.1 mg/Kg to about 500mg/Kg, alternatively from about 1 to about 50 mg/Kg. In general,treatment regimens according to the present application compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this application per day insingle or multiple doses. Therapeutic amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this application may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present application will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The application also provides for a pharmaceutical combinations, e.g., akit, comprising a) a first agent which is a compound of the applicationas disclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time.

The term “pharmaceutical combination” as used herein means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g., a compound of the application and a co-agent, areboth administered to a patient simultaneously in the form of a singleentity or dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of the application and a co-agent, are bothadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific time limits, wherein suchadministration provides therapeutically effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g., the administration of three or more activeingredients.

In certain embodiments, these compositions optionally further compriseone or more additional therapeutic agents. For example, chemotherapeuticagents or other antiproliferative agents may be combined with thecompounds of this application to treat proliferative diseases andcancer. Examples of known chemotherapeutic agents include, but are notlimited to, Gleevec™, adriamycin, dexamethasone, vincristine,cyclophosphamide, fluorouracil, topotecan, taxol, interferons, andplatinum derivatives.

Other examples of agents the compounds of this application may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept18 and Excelon®; treatments for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole,bromocriptine, pergolide, trihexephendyl, and amantadine; agents fortreating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such asalbuterol and Singulair®; agents for treating schizophrenia such aszyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agentssuch as corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and antiparkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,antileukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylenepolyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes, oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate, agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The protein kinaseinhibitors or pharmaceutical salts thereof may be formulated intopharmaceutical compositions for administration to animals or humans.These pharmaceutical compositions, which comprise an amount of theprotein inhibitor effective to treat or prevent a proteinkinase-mediated condition and a pharmaceutically acceptable carrier, areanother embodiment of the present application.

In another aspect, the application provides a kit comprising a compoundcapable of inhibiting kinase activity selected from one or morecompounds of Formula (I′), or pharmaceutically acceptable salts,hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, andinstructions for use in treating cancer. In certain embodiments, the kitfurther comprises components for performing a test to determine whethera subject has activating and/or drug resistance mutations in EGFR.

In another aspect, the application provides a kit comprising a compoundcapable of inhibiting EGFR activity selected from a compound of thepresent disclosure, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

EXAMPLES Analytical Methods, Materials, and Instrumentation

All reactions were monitored by Waters LC/MS system (Waters 2998Photodiode Array Detector, Waters SQ detector 2, Waters 515 HPLC pump,Waters 2545 Binary Gradient Module, Waters System Fluidics Organizer andWaters 2767 Sample Manager) using SunFire™ C18 column (4.6×50 mm, 5 μmparticle size): method A—solvent gradient=75% A at 0 min, 1% A at 5 min;solvent A=0.035% TFA in Water; solvent B=0.035% TFA in MeOH; flow rate:1.8 mL/min) and method B—solvent gradient=80% A at 0 min, 1% A at 5 min;solvent A=0.035% TFA in Water; solvent B=0.035% TFA in MeOH; flow rate:1.5 mL/min or Waters Acquity UPLC/MS system (Waters PDA e2 Detector, QDaDetector, Sample manager—FL, Binary Sovent Manager) using Acquity UPLC®BEH C18 column (2.1×50 mm, 1.7 μm particle size): solvent gradient=80% Aat 0 min, 5% A at 2 min; solvent A=0.1% formic acid in Water; solventB=0.1% formic acid in Acetonitrile; flow rate: 0.6 mL/min (method C).Reaction products were purified by flash column chromatography usingCombiFlash®Rf with Teledyne Isco RediSep®Rf High Performance Gold orSilicycle SiliaSep™ High Performance columns (4 g, 12 g, 24 g, 40 g, or80 g) and Waters LC/MS system using SunFire™ Prep C18 column (19×50 mm,5 μm particle size): solvent gradient=80% A at 0 min, 10% A at 8 min;solvent A=0.035% TFA in Water; solvent B=0.035% TFA in MeOH; flow rate:25 mL/min. The purity of all compounds was over 95% and was analyzedwith Waters LC/MS system. ¹H NMR was obtained using a 600 MHz VarianInova-600 or 400 MHz Varian. Chemical shifts are reported relative tochloroform (6=7.24) or dimethyl sulfoxide (6=2.50) for ¹H NMR anddimethyl sulfoxide (δ=39.51) for ¹³C NMR. Data are reported as(br=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet).

Abbreviations Used in the Following Examples and Elsewhere Herein are

-   -   atm atmosphere    -   br broad    -   DIPEA N,N-diisopropylethylamine    -   DMA N,N-dimethylacetamide    -   DMF N,N-dimethylformamide    -   ESI electrospray ionization    -   h hour(s)    -   HPLC high-performance liquid chromatography    -   LCMS liquid chromatography-mass spectrometry    -   m multiplet    -   MHz megahertz    -   min minutes    -   NMR nuclear magnetic resonance    -   ppm parts per million    -   TLC thin layer chromatography

Example 1: 3-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate(I-2)

Step 1. 3-fluorobenzyl (3-nitrophenyl)carbamate

To a solution of 3-fluorobenzyl alcohol (0.66 μL, 6.09 mmol) and3-nitrophenyl isocyanate (1 g, 6.09 mmol) in dioxane (10 mL) was addedtrimethylamine (1.7 mL, 12.19 mmol). After stirring for 1 hr at 60° C.,the reaction mixture was concentrated in vacuo and the residue wasdissolved in EtOAc. The desire product was then crystallized usinghexane. The crystallized product was isolated via filtration and thesolid was washed with hexane to obtain 3-fluorobenzyl(3-nitrophenyl)carbamate as an yellow solid. (750 mg, 42.5% yield).

Step 2. 3-fluorobenzyl (2-chloropyrimidin-4-yl)(3-nitrophenyl)carbamate

To a solution of 3-fluorobenzyl carbamate (400 mg, 1.38 mmol) and2,4-dichloropyrimidine (Step 1, 308 mg, 2.07 mmol) inN,N-dimethylformamide (5 mL) was added sodium hydride (83 mg, 2.07 mmol)at 0° C. After stirring for 2 hr at room temperature, the reactionmixture was cooled down to 0° C., diluted with EtOAc and carefullyquenched with water. The resulting mixture was then washed with waterfive times and the combined organic layers were dried over sodiumsulfate, filtered and concentrated in vacuo. The resulting residue waspurified using SCO Column Chromatography on a silica column (1:99 to50:50, EtOAc/CH₂Cl₂) to obtain 3-fluorobenzyl(3-aminophenyl)(2-chloropyrimidin-4-yl)carbamate as a sticky oil (410mg, 79.9% yield).

Step 3. 3-fluorobenzyl(3-acrylamidophenyl)(2-chloropyrimidin-4-yl)carbamate

To a solution of 3-fluorobenzyl(2-chloropyrimidin-4-yl)(3-nitrophenyl)carbamate (Step 2, 450 mg) inethyl acetate (10 mL) was added tin(II) chloride dehydrate (1.3 g) andconc. HCl (1.0 mL). After stirring for 2 h at room temperature, thereaction mixture was diluted with ethyl acetate and then neutralizedwith saturated sodium bicarbonate. The resulting mixture was washed withwater two times, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was used next step withoutfurther purification.

Step 4. 3-fluorobenzyl(3-acrylamidophenyl)(2-chloropyrimidin-4-yl)carbamate

Crude 3-fluorobenzyl-(3-aminophenyl)-(2-chloropyrimidin-4-yl)carbamate(Step 3) was dissolved in a 1:1 mixture of tetrahydrofuran (5 mL) andsaturated NaHCO₃ (5 mL). Acryloyl chloride (125 μL) was then added tothe reaction mixture and the resulting solution was stirred for 30 min.The resulting mixture was diluted with ethyl acetate, washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The resulting residue was purified via ISCO ColumnChromatography on a silica column (1:99 to 50:50=CH₂Cl₂/EtOAc) to obtain3-fluorobenzyl (3-acrylamidophenyl)(2-chloropyrimidin-4-yl)carbamate(277 mg, 58% yield over two steps) as an off-white solid.

Step 5. 3-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate

To a solution of 3-fluorobenzyl(3-acrylamidophenyl)(2-chloropyrimidin-4-yl)carbamate (Step 4, 80 mg,0.19 mmol) in 2-butanol was added 1-methyl-1H-pyrazol-3-amine (27 mg,0.28 mmol) and trifluoroacetic acid (22 μL, 0.28 mmol) and the resultingmixture was heated to 80° C. After stirring for 4 hr, the reactionmixture was cooled down to room temperature and diluted with EtOAc. Theorganic layer was washed with water, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resulting residuewas purified via preparative high performance liquid chromatography(HPLC) to obtain 3-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate(I-2, 71 mg, 78% yield) as a white solid. ¹H NMR 400 MHz (DMSO-d₆) δ10.19 (s, 1H), 9.74 (s, 1H), 8.30 (d, J=5.6 Hz, 1H), 7.63 (d, J=7.6 Hz,1H), 7.59 (t, J=2.0 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.31 (d, J=5.6 Hz,1H), 7.32-7.26 (m, 1H), 7.10 (bs, 1H), 7.06-6.99 (m, 3H), 6.92 (d,J=10.0 Hz, 1H), 6.34 (dd, J=16.8, 10.0 Hz, 1H), 6.18 (dd, J=16.8, 2.0Hz, 1H), 5.69 (dd, J=10.4, 2.0 Hz, 1H), 5.39 (bs, 1H), 5.16 (s, 2H),3.57 (s, 3H). Method B: Rt=4.55 min, MS m/z: 488.33 [M+1]

The following compounds in Table 1 were synthesized according to theprocedure outlined for Compound I-2 in Example 1.

TABLE 1 Compound Number ¹H NMR and or MS (m/z) data I-1 Method A: Rt =3.68 min, MS m/z: 470.96 [M + 1] ¹H NMR 400 MHz (DMSO-d₆) δ 10.25 (s,1H), 9.84 (s, 1H), 8.36 (d, J = 5.9 Hz, 1H), 7.69 (d, J = 8.7 Hz, 1H),7.67 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 5.9 Hz, 1H),7.35-7.28 (m, 3H), 7.25-7.21 (m, 2H), 7.18 (s, 1H), 7.05 (d, J = 7.9 Hz,1H), 6.41 (dd, J = 17.0, 10.1 Hz, 1H), 6.25 (dd, J = 17.0, 2.0 Hz, 1H),5.76 (dd, J = 10.0, 1.9 Hz, 1H), 5.45 (bs, 1H), 5.22 (s, 2H), 3.64 (s,3H). I-2 Method B: Rt = 4.55 min, MS m/z: 488.33 [M + 1] ¹H NMR 400 MHz(DMSO-d₆) δ 10.19 (s, 1H), 9.74 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.63(d, J = 7.6 Hz, 1H), 7.59 (t, J = 2.0 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H),7.31 (d, J = 5.6 Hz, 1H), 7.32-7.26 (m, 1H), 7.10 (bs, 1H), 7.06-6.99(m, 3H), 6.92 (d, J = 10.0 Hz, 1H), 6.34 (dd, J = 16.8, 10.0 Hz, 1H),6.18 (dd, J = 16.8, 2.0 Hz, 1H), 5.69 (dd, J = 10.4, 2.0 Hz, 1H), 5.39(bs, 1H), 5.16 (s, 2H), 3.57 (s, 3H). I-3 Method B: Rt = 4.67 min, MSm/z: 488.33 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.34 (s, 1H), 9.48 (s,1H), 8.32 (d, J = 5.4 Hz, 1H), 7.80-7.75 (m, 1H), 7.72 (s, 1H),7.55-7.50 (m, 1H), 7.42 (s, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.14-7.07 (m,2H), 7.04 (d, J = 7.8 Hz, 1H), 7.01 (s, 1H), 6.96 (d, J = 9.6 Hz, 1H),6.46 (s, 1H), 6.40 (dd, J = 16.8, 6.8 Hz, 1H), 6.23 (dd, J = 16.8, 1.2Hz, 1H), 5.75 (dd, J = 9.6, 1.8 Hz, 1H), 5.21 (s, 2H), 3.49 (s, 3H). I-4Method B: Rt = 4.59 min, MS m/z: 488.33 [M + 1] ¹H NMR 600 MHz (DMSO-d₆)δ 10.23 (s, 1H), 9.82 (s, 1H), 8.34 (d, J = 6.0 Hz, 1H), 7.66 (d, J =7.8 Hz, 1H), 7.59 (t, J = 1.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.34(d, J = 6.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.18-7.13 (m, 1H), 7.12-7.10 (m,2H), 7.02-7.01 (m, 1H), 6.39 (dd, J = 16.8, 10.2 Hz, 1H), 6.24 (dd, J =16.8, 1.2 Hz, 1H), 5.74 (dd, J = 9.6, 1.2 Hz, 1H), 5.42 (bs, 1H), 5.18(s, 2H), 3.62 (s, 3H). I-5 Method B: Rt = 4.68 min, MS m/z: 488.33 [M +1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.46 (s, 1H), 9.48 (s, 1H), 8.31 (d, J =5.4 Hz, 1H), 7.75 (m, 1H), 7.67 (s, 1H), 7.50 (m, 1H), 7.39 (s, 1H),7.29-7.25 (m, 2H), 7.15-7.10 (m, 2H), 7.07 (d, J = 6.0 Hz, 1H), 7.01 (s,1H), 6.45 (bs, 1H), 6.40 (dd, J = 17.4, 10.8 Hz, 1H), 6.24 (dd, J =16.8, 1.8 Hz, 1H), 5.75 (dd, J = 9.6, 1.8 Hz, 1H), 5.18 (s, 2H), 3.49(s, 3H). I-6 Method B: Rt = 4.78 min, MS m/z: 526.33 [M + 1] ¹H NMR 600MHz (DMSO-d₆) δ 10.24 (s, 1H), 9.73 (s, 1H), 8.35 (d, J = 6.0 Hz, 1H),7.91 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.2 Hz,1H), 7.57 (s, 1H), 7.42-7.38 (m, 2H), 7.37-7.31 (m, 3H), 7.11 (s, 1H),7.01 (d, J = 7.8 Hz, 1H), 6.38 (dd, J = 16.8, 9.6 Hz, 1H), 6.23 (dd, J =17.4, 1.8 Hz, 1H), 5.73 (dd, J = 10.2, 1.2 Hz, 1H), 5.48 (s, 2H), 5.42(bs, 1H), 3.61 (s, 3H). I-7 Method B: Rt = 4.97 min, MS m/z: 526.33 [M +1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.32 (s, 1H), 9.48 (s, 1H), 8.33 (d, J =5.4 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 5.4 Hz, 1H), 7.79(d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.50 (m, 1H), 7.44-7.38 (m, 2H),7.37-7.32 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.46 (s, 1H),6.39 (dd, J = 16.8, 10.2 Hz, 1H), 6.23 (dd, J = 16.8, 1.8 Hz, 1H), 5.74(dd, J = 9.6, 1.8 Hz, 1H), 5.48 (s, 2H), 3.48 (s, 3H). I-8 Method B: Rt= 4.12 min, MS m/z: 504.45 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.25 (s,1H), 9.62 (s, 1H), 8.33 (d, J = 6.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H),7.60-7.58 (m, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H),7.28 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.11 (s, 1H), 7.03(dd, J = 8.4, 1.2 Hz, 1H), 6.40 (dd, J = 17.4, 10.8 Hz, 1H), 6.24 (dd, J= 16.2, 1.8 Hz, 1H), 5.74 (dd, J = 9.6, 1.2 Hz, 1H), 5.42 (bs, 1H), 5.19(s, 2H), 3.60 (s, 3H). I-9 Method B: Rt = 4.22 min, MS m/z: 504.32 [M +1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.32 (s, 1H), 9.41 (s, 1H), 8.31 (d, J =5.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.68 (s, 1H), 7.53-7.47 (m, 1H),7.40-7.35 (m, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H),7.09 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.45 (bs, 1H), 6.40 (dd, J =16.8, 10.2 Hz, 1H), 6.24 (dd, J = 16.8, 2.4 Hz, 1H), 5.75 (dd, J = 9.6,1.8 Hz, 1H), 5.19 (s, 2H), 3.49 (s, 3H). I-10 Method B: Rt = 3.45 min,MS m/z: 489.35 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.24 (s, 1H), 9.62(s, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.33 (d, J = 5.4 Hz, 1H), 7.70-7.66(m, 2H), 7.61 (t, J = 1.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.30 (d, J= 4.8 Hz, 1H), 7.28 (q, J = 4.2 Hz, 1H), 7.11 (s, 1H), 7.08 (dd, J =8.4, 1.2 Hz, 1H), 6.39 (dd, J = 17.4, 10.2 Hz, 1H), 6.24 (dd, J = 16.8,1.2 Hz, 1H), 5.74 (dd, J = 9.6, 1.2 Hz, 1H), 5.42 (bs, 1H), 5.25 (s,2H), 3.61 (s, 3H). I-11 Method B: Rt = 3.54 min, MS m/z: 489.35 [M + 1]¹H NMR 600 MHz (DMSO-d₆) δ 10.36 (s, 1H), 9.42 (s, 1H), 8.52 (d, J = 3.0Hz, 1H), 8.31 (d, J = 5.4 Hz, 1H), 7.80-7.75 (m, 1H), 7.72-7.66 (m, 2H),7.52-7.48 (m, 1H), 7.40-7.36 (m, 1H), 7.28-7.24 (m, 1H), 7.15-7.11 (m,1H), 7.01 (s, 1H), 6.46 (bs, 1H), 6.41 (dd, J = 16.8, 10.2 Hz, 1H), 6.24(dd, J = 16.8, 2.4 Hz, 1H), 5.75 (dd, J = 9.6, 1.8 Hz, 1H), 5.25 (s,2H), 3.49 (s, 3H). I-12 Method B: Rt = 3.34 min, MS m/z: 489.35 [M + 1]¹H NMR 600 MHz (DMSO-d₆) δ 10.24 (s, 1H), 9.61 (s, 1H), 8.33 (d, J = 5.4Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.87 (td, J = 8.4, 2.4 Hz, 1H), 7.67(d, J = 8.4 Hz, 1H), 7.58 (t, J = 1.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H),7.28 (d, J = 5.4 Hz, 1H), 7.14 (dd, J = 9.0, 3.0 Hz, 1H), 7.11 (s, 1H),7.03 (dt, J = 7.2, 1.2 Hz, 1H), 6.41 (dd, J = 16.8, 10.2 Hz, 1H), 6.24(dd, J = 16.8, 2.4 Hz, 1H), 5.75 (dd, J = 9.6, 1.8 Hz, 1H), 5.40 (bs,1H), 5.24 (s, 2H), 3.60 (s, 3H). I-13 Method B: Rt = 3.48 min, MS m/z:489.35 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.37 (s, 1H), 9.41 (s, 1H),8.32 (d, J = 5.4 Hz, 1H), 8.09 (s, 1H), 7.86 (t, J = 6.6 Hz, 1H), 7.76(m, 1H), 7.67 (s, 1H), 7.50 (m, 1H), 7.40 (s, 1H), 7.14 (dd, J = 8.4,2.4 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.45 (bs, 1H), 6.41(dd, J = 16.8, 10.2 Hz, 1H), 6.24 (dd, J = 16.8, 1.2 Hz, 1H), 5.75 (dd,J = 9.6, 1.8 Hz, 1H), 5.24 (s, 2H), 3.49 (s, 3H). I-14 Method B: Rt =3.93 min, MS m/z: 502.40 [M + 1] I-15 Method B: Rt = 4.78 min, MS m/z:502.34 [M + 1] I-16 Method B: Rt = 3.98 min, MS m/z: 502.40 [M + 1] I-17Method B: Rt = 4.77 min, MS m/z: 502.34 [M + 1] I-18 Method B: Rt = 4.05min, MS m/z: 526.33 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.20 (s, 1H),9.63 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.67(s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.57 (s,1H), 7.36-7.26 (m, 4H), 7.10 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.39(dd, J = 16.8, 10.8 Hz, 1H), 6.24 (dd, J = 16.8, 1.8 Hz, 1H), 5.74 (dd,J = 10.2, 1.8 Hz, 1H), 5.44 (s, 2H), 5.41 (bs, 1H), 3.60 (s, 3H). I-19Method B: Rt = 4.15 min, MS m/z: 526.33 [M + 1] ¹H NMR 600 MHz (DMSO-d₆)δ 10.28 (s, 1H), 9.40 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 7.94 (d, J =8.4 Hz, 1H), 7.76-7.70 (m, 1H), 7.66 (s, 2H), 7.60 (d, J = 7.2 Hz, 1H),7.47-7.38 (m, 2H), 7.34 (t, J = 6.6 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H),7.04 (d, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.44 (bs, 1H), 6.39 (dd, J =17.4, 10.2 Hz, 1H), 6.24 (dd, J = 16.8, 1.8 Hz, 1H), 5.75 (dd, J = 9.6,1.8 Hz, 1H), 5.44 (s, 2H), 3.47 (s, 3H). I-20 Method A: Rt = 3.17 min,MS m/z: 587.59 I-21 Method A: Rt = 4.02 min, MS m/z: 502.54 [M + 1] ¹HNMR 600 MHz (DMSO-d₆) δ 10.30 (s, 1H), 8.82 (bs, 1H), 8.32 (d, J = 5.6Hz, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.50-7.45 (m, 1H), 7.35 (s, 1H),7.27 (t, J = 6.8 Hz, 1H), 7.12 (t, J = 8.9 Hz, 1H), 7.04 (d, J = 7.7 Hz,1H), 6.39 (dd, J = 16.9, 10.2 Hz, 1H), 6.37 (bs, 1H), 6.24 (dd, J =16.9, 1.8 Hz, 1H), 5.75 (dd, J = 10.0, 1.8 Hz, 1H), 5.17 (s, 2H), 3.40(s, 3H), 2.02 (s, 3H). I-22 Method A: Rt = 3.69 min, MS m/z: 502.54 [M +1]. I-23 Method A: Rt = 4.61 min, MS m/z: 556.51 [M + 1]. I-24 Method A:Rt = 3.28 min, MS m/z: 585.57 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.22(s, 1H), 9.40 (s, 1H), 8.30 (d, J = 5.1 Hz, 1H), 7.73 (s, 1H), 7.66 (s,1H), 7.52-7.45 (m, 1H), 7.37 (s, 1H), 7.27 (t, J = 7.5 Hz, 2H), 7.12 (t,J = 8.9 Hz, 2H), 7.05 (d, J = 7.4 Hz, 1H), 7.00 (s, 1H), 6.72 (dt, J =15.4, 5.9 Hz, 1H), 6.44 (s, 1H), 6.21 (d, J = 15.4 Hz, 1H), 5.17 (s,2H), 3.48 (s, 3H), 3.04 (d, J = 5.6 Hz, 2H), 2.31 (s, 4H), 1.48 (quint,J = 5.6 Hz, 4H), 1.39-1.34 (m, 2H). I-25 Method A: Rt = 3.30 min, MSm/z: 601.58 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.22 (s, 1H), 9.40 (s,1H), 8.30 (d, J = 5.2 Hz, 1H), 7.73 (d, J = 6.7 Hz, 1H), 7.66 (s, 1H),7.52-7.45 (m, 1H), 7.37 (s, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.12 (t, J =8.9 Hz, 2H), 7.05 (d, J = 7.0 Hz, 1H), 7.00 (s, 1H), 6.71 (dt, J = 15.4,5.8 Hz, 1H), 6.44 (s, 1H), 6.21 (d, J = 15.4 Hz, 1H), 5.17 (s, 2H), 4.53(d, J = 4.0 Hz, 1H), 3.48 (s, 3H), 3.42 (bs, 1H), 3.06 (d, J = 5.0 Hz,2H), 2.68-2.63 (m, 2H), 2.02 (d, J = 10.1 Hz, 2H), 1.71-1.66 (m, 2H),1.41-1.34 (m, 2H). I-26 Method A: Rt = 3.30 min, MS m/z: 587.56 [M + 1]¹H NMR 600 MHz (DMSO-d₆) δ 10.25 (s, 1H), 9.40 (s, 1H), 8.30 (d, J = 5.2Hz, 1H), 7.73 (d, J = 5.3 Hz, 1H), 7.66 (s, 1H), 7.52-7.45 (m, 1H), 7.37(s, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 8.9 Hz, 2H), 7.05 (d, J= 6.8 Hz, 1H), 7.00 (s, 1H), 6.70 (dt, J = 15.4, 5.9 Hz, 1H), 6.44 (s,1H), 6.24 (d, J = 15.4 Hz, 1H), 5.17 (s, 2H), 3.67 (d, J = 4.4 Hz, 4H),3.48 (s, 3H), 3.09 (dd, J = 5.8, 1.0 Hz, 2H), 2.36 (s, 4H). I-27 MethodA: Rt = 3.41 min, MS m/z: 599.60 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ10.21 (s, 1H), 9.40 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 5.6Hz, 1H), 7.66 (s, 1H), 7.52-7.45 (m, 1H), 7.37 (s, 1H), 7.27 (t, J = 6.8Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 7.05 (d, J = 7.1 Hz, 1H), 7.00 (s,1H), 6.73 (dt, J = 15.3, 5.7 Hz, 1H), 6.45 (s, 1H), 6.23 (d, J = 15.4Hz, 1H), 5.18 (s, 2H), 3.49 (s, 3H), 3.23 (d, J = 5.1 Hz, 2H), 2.55 (t,J = 5.3 Hz, 4H), 1.60-1.52 (m, 8H). I-28 Method A: Rt = 3.26 min, MSm/z: 545.59 [M + 1] ¹H NMR 600 MHz (DMSO-d₆) δ 10.24 (s, 1H), 9.41 (s,1H), 8.30 (d, J = 5.1 Hz, 1H), 7.75-7.70 (m, 1H), 7.67 (s, 1H),7.52-7.45 (m, 1H), 7.37 (s, 1H), 7.27 (t, J = 6.6 Hz, 2H), 7.13 (t, J =8.9 Hz, 2H), 7.08-7.02 (m, 1H), 7.00 (s, 1H), 6.71 (dt, J = 15.4, 5.9Hz, 1H), 6.44 (s, 1H), 6.23 (d, J = 15.4 Hz, 1H), 5.18 (s, 2H), 3.48 (s,3H), 3.4-3.01 (m, 2H), 2.14 (s, 6H). I-29 Method C: Rt = 0.82 min, MSm/z: 505.98 [M + 1] ¹H NMR 500 MHz (DMSO-d₆) δ 10.32 (s, 1H), 9.43 (s,1H), 8.32 (d, J = 5.5 Hz, 1H), 7.80-7.72 (m, 1H), 7.65 (s, 1H),7.54-7.46 (m, 1H), 7.40-7.31 (m, 2H), 7.24 (td, J = 10.4, 2.8 Hz, 1H),7.08-6.98 (m, 3H), 6.46 (bs, 1H), 6.40 (dd, J = 10.4, 17.1 Hz, 1H), 6.25(dd, J = 1.8, 16.8 Hz, 1H), 5.78-5.75 (m, 1H), 5.23 (s, 2H), 3.50 (s,3H). I-30 Method C: Rt = 0.82 min, MS m/z: 571.01 [M + 1] ¹H NMR 500 MHz(DMSO-d₆) δ 10.40 (s, 1H), 9.51 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.99(d, J = 6.4 Hz, 1H), 7.61-7.49 (m, 2H), 7.43-7.38 (m, 1H), 7.33-7.26 (m,2H), 7.19-7.10 (m, 4H), 6.53 (bs, 1H), 6.43 (dd, J = 10.1, 16.8 Hz, 1H),6.32-6.24 (m, 1H), 5.82-5.76 (m, 1H), 5.20 (s, 2H), 3.78 (m, 1H), 3.55(d, J = 11.9 Hz, 2H), 3.25-3.12 (m, 2H), 2.86 (d, J = 3.1 Hz, 3H), 2.07(q, J = 12.2 Hz, 2H), 1.93-1.80 (m, 2H). I-31 Method C: Rt = 0.82 min,MS m/z: 544.96 [M + 1] ¹H NMR 500 MHz (DMSO-d₆) δ 10.27 (s, 1H), 9.51(s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 7.75-7.69 (m, 2H), 7.66-7.57 (m, 2H),7.46-7.35 (m, 2H), 7.33-7.26 (m, 2H), 7.16-7.11 (m, 2H), 7.09-7.02 (m,2H), 6.60 (bs, 1H), 6.39 (dd, J = 10.1, 16.8 Hz, 1H), 6.24 (dd, J = 1.8,16.8 Hz, 1H), 5.75 (dd, J = 2.1, 10.1 Hz, 1H), 5.19 (s, 2H), 4.38 (s,2H), 2.58 (d, J = 4.6 Hz, 3H). I-32 Method C: Rt = 0.68 min, MS m/z:556.98 [M + 1]

Example 2: Biochemical Studies Kinase Inhibitors

WZ4002, AZD9291 and CO-1686 were synthesized using previously publishedmethods (Zhou, W., et al., Nature 462, 2009, 1070-4; Walter, A. O., etal., Cancer Discov. 3, 2013, 1404-15; Cross, D. A., et al., CancerDiscov. 2014). Dacomitinib, Afatinib, and Neratinib were obtained fromSelleck chemicals. Stock solutions of all drugs were prepared in DMSOand stored at −80° C.

Cell Culture and Reagents Generation of EGFR Exon 20 Insertion MutationBa/F3 Cells

Different EGFR exon 20 insertion mutations were introduced via sitedirected mutagenesis into full length EGFR using the Quick ChangeSite-Directed Mutagenesis kit (Stratagene; La Jolla, Calif.) accordingto the manufacturer's instructions. All constructs were confirmed by DNAsequencing. The constructs were shuttled into the retroviral vectorJP1540 using the BD Creator™ System (BD Biosciences). Parental Ba/F3cells were infected with the retroviral constructs described previously(Zhou et al. Nature 2009). Stable clones were obtained by selection inpuromycin (2 μg/ml) and growth in IL-3 free media. The following EGFRexon 20 insertion Ba/F3 cells used in the studies:

Cell Line Name Amino Acid Change Nucleotide Change Ins GY D770delinsGY2308_2309InsGTT Ins SVD D770_N771insSVD 2301_2309DupCAGCGTGGA Ins ASVV769_D770insASV 2297_2305DupTGGCCAGCG Ins HH Y764_V765insHH2290_2291InsACCATC Ins H H773dupH 2316_2317InsCAC

Generation of EGFR Exon 20 Insertion Patient Derived Cell Lines

Two primary patient derived cell lines from EGFR mutant advanced NSCLCpatients known to harbor an EGFR exon 20 insertion mutation weregenerated. The studies were performed under an IRB approved protocol andboth patients provided written informed consent. The cell lines andtheir respective mutations are shown below:

Cell Line Name Amino Acid Change Nucleotide Change DFCI 58H773_V774insNPH 2311_2319dupAACCCCCAC DFCI 127 P772_H773insPNP2317_2318insCGAACCCCC

Cell Proliferation Assays and Growth Assays

Murine Ba/F3 cells engineered to express mutant and wild type EGFR orHER2 protein were used to perform single drug screens. Cell viabilitywas assessed after 72 hours of compound exposure using the colorimetriccell proliferation MTS assay kit (Promega).

Growth and inhibition of growth was assessed by MTS assay and wasperformed according to published methods ((Zhou, W., et al., Nature.462, 2009, 1070-4; Ercan, D., et al., Cancer Discov. 934, 2012, 934-47).Non-small cell lung cancer (NSCLC) cell lines or Ba/F3 cells harboringspecific exon 20 insertion mutations were exposed to treatment for 72hours and the number of cells used per experiment determined empiricallyand has been previously established (Zhou et al. Nature 2009). Allexperimental points were set up in six wells and all experiments wererepeated at least three times. The data was graphically displayed usingGraphPad Prism version 5.0 for Windows, (GraphPad Software;www.graphpad.com). The curves were fitted using a non-linear regressionmodel with a sigmoidal dose response.

Table 2 shows the inhibition data of an EGFR wild type Ba/F3 cell line,a EGFR InsGY Ba/F3 cell line, a EGFR InsSVD Ba/F3 cell line, and a EGFRInsASV Ba/F3 cell line treated with compounds of the present disclosure.++++ indicates an EC₅₀ less than 100 nM, +++ indicates an EC₅₀ betweenabout 100 nM to about 500 nM, ++ indicates a EC₅₀ between about 500 nMto about 1000 nM, and + indicates an EC₅₀ of greater than 1000 nM.

TABLE 2 Wild Compound type (nM) InsGY (nM) InsSVD (nM) InsASV (nM) I-1++++ ++++ ++++ +++ I-2 ++++ ++++ ++++ n/a I-3 ++++ ++++ ++++ n/a I-4++++ ++++ ++++ n/a I-5 ++++ ++++ ++++ n/a I-6 ++ +++ ++ n/a I-7 +++ +++++++ n/a I-8 +++ +++ + + I-9 ++++ +++ +++ ++ I-10 ++++ ++ +++ ++ I-11++++ ++ ++ + I-12 +++ ++ ++ + I-13 +++ + + + I-14 +++ ++ ++ + I-15 ++++++++ ++++ +++ I-16 ++++ +++ +++ ++ I-17 ++++ ++++ ++++ +++ I-18 + + n/an/a I-19 +++ + + + I-20 ++++ ++++ +++ n/a I-21 ++++ ++++ ++++ n/a I-22++++ ++++ ++++ n/a I-23 ++++ +++ +++ n/a I-24 ++++ +++ ++ n/a I-25 +++n/a n/a n/a I-26 ++++ +++ ++ n/a I-27 ++++ ++ ++ n/a I-28 ++++ ++ + n/aI-29 ++++ ++++ ++++ n/t I-30 ++++ ++++ ++++ n/t I-31 ++++ +++ +++ n/tI-32 ++++ ++++ ++++ n/t Dacomitinib ++++ ++++ + + Neratinib ++++ +++ +++ Afatinib ++++ ++++ ++ ++ WZ4002 + ++ + + AZD9291 ++ +++ ++ ++CO1686 + + + +

Table 3 shows the inhibition data of a HER2 wild type Ba/F3 cell lineand a HER2 InsYVMA Ba/F3 cell line treated with compounds of the presentdisclosure. ++++ indicates an EC₅₀ less than 100 nM, +++ indicates anEC₅₀ between about 100 nM to about 500 nM, ++ indicates a EC₅₀ betweenabout 500 nM to about 1000 nM, and + indicates an EC₅₀ of greater than1000 nM.

TABLE 3 Compound Number Wild type (nM) insYVMA (nM) I-1 ++++ ++++ I-2++++ +++ I-3 ++++ ++++ I-4 ++++ ++++ I-5 ++++ ++++ I-6 ++ + I-7 +++ ++I-8 +++ + I-9 ++++ +++ I-10 +++ ++ I-11 +++ ++ I-12 +++ + I-13 +++ +I-14 ++ n/a I-15 ++++ +++ I-16 ++++ ++ I-17 ++++ ++++ I-18 + n/a I-19+++ + I-20 ++++ ++++ I-21 ++++ ++++ I-22 ++++ ++++ I-23 ++++ +++ I-24++++ ++++ I-25 +++ + I-26 ++++ +++ I-27 ++++ ++++ I-28 ++++ ++++ I-29++++ ++++ I-30 ++++ ++++ I-31 ++++ ++++ I-32 ++++ ++++ Dacomitinib ++++++++ Neratinib ++++ ++++ Afatinib ++++ ++++ WZ4002 +++ + AZD9291 ++++ ++

Antibodies and Western Blotting

Cells grown under the previously specified conditions were lysed inNP-40 buffer (Cell Signaling Technology). Western blot analyses wereconducted after separation by SDS/PAGE electrophoresis and transfer topolyvinylidene difluoride-P membrane (Millipore). Immunoblotting wasperformed according to the antibody manufacturers' recommendations.Antibody binding was detected using an enhanced chemiluminescence system(Perkin Elmer Inc.). Anti-phospho-EGFR, anti-total EGFR antibodies wereobtained from Cell Signaling Technology. Tubulin antibody was purchasedfrom Sigma. FIG. 1 and FIG. 2 are Western blots showing the levels ofpEGFR, EGFR, and tubulin in cells having wild type EGFR or mutant EGFRafter treatment with Compound I-1 (FIGS. 1A and 1B), Compound I-5 (FIGS.2A and 2B), dacomitinib, WZ4002, or AZD9291 for 24 hours.

Generation of Mouse Cohorts and Treatment with Compounds of the PresentDisclosure

EGFR-exon 20 insertion mice are generated and characterized. Exon 20mutations were introduced via site directed mutagenesis into full lengthEGFR using the Quick Change Site-Directed Mutagenesis kit (Stratagene;La Jolla, Calif.) according to the manufacturer's instructions. Allconstructs were confirmed by DNA sequencing. The constructs wereshuttled into the retroviral vector JP1540 using the BD Creator™ System(BD Biosciences). Transgenic mice are then generated by injection of theconstruct into FVB/N fertilized eggs. Progeny are genotyped through PCRexactly the same as reported. Founders are crossed with CCSP-rtTA miceand inducible bitransgenic mice with high and inducible expression ofthe mutant hEGFR transgene are identified and expanded for subsequentanalyses and experiments. All mice are housed in a pathogen-freeenvironment at the Harvard School of Public Health and are handled instrict accordance with Good Animal Practice as defined by the Office ofLaboratory Animal Welfare, and all animal work is done with Dana-FarberCancer Institute IACUC approval.

Cohorts of EGFR-exon 20 insertion/CCSP-rtTA are put on doxycycline dietat 5 weeks of age to induce the expression of mutant EGFR. These miceundergo MRI after 6 to 8 weeks of doxycycline diet to document andquantify the lung cancer burden before being assigned to varioustreatment study cohorts. There is a minimum of 3 mice per treatmentgroup. Mice are then treated either with vehicle (NMP (10%1-methyl-2-pyrrolidinone: 90% PEG-300) alone or a compound disclosedherein at 25 mg/kg gavage daily. After 2 weeks of treatment, these miceundergo a second round of MRI to document their response to thetreatment. MRIs and tumor burden measurement are performed as describedpreviously (Li, D. et al. Cancer Cell 12, 81-93 (2007); Ji, H. et al.Cancer Cell 9, 485-95 (2006)).

MRI Scanning and Tumor Volume Measurement

Mice are anesthetized with 1% isoflurane in an oxygen/air mixture. Therespiratory and cardiac rates of anesthetized mice are monitored usingBiotrig Software. The animals are imaged with a rapid acquisition withrelaxation enhancement (RARE) sequence (TR=2000 ms, TE effect=25 ms) inthe coronal and axial planes with a 1 mm slice thickness and withsufficient number of slices to cover the entire lung. Matrix size of128×128 and a field of view (FOV) of 2.5 cm×2.5 cm² are used for allimaging. With same geometry and described above, the mice are alsoimaged with a gradient echo fast imaging (GEFI) sequence (TR=180 ms, TEeffect=2.2 ms) with respiratory and cardiac gating, in both coronal andaxial planes. The detailed procedure for MRI scanning has beenpreviously described (Li, D. et al. Cancer Cell 12, 81-93 (2007); Ji, H.et al. Cancer Cell 9, 485-95 (2006)).

Immunohistochemical Analyses

Hematoxylin and eosin (H&E) staining of tumor sections is performed atthe Department of Pathology at the Brigham and Women's Hospital.Immunohistochemistry is performed on formal fixed paraffin embeddedtumor sections. The antibodies used are: total EGFR and phospho-EGFRY1068 (Cell Signaling Technology) and Ki67. Apoptosis is measured bycounting nuclear bodies in H&E stained sections and by a terminaldeoxynucleotidyl-transferase mediated dUTP-biotin nick end labeling(TUNEL) assay.

Pharmacokinetic Analyses

Dose administration: All mice are weighed before dose administration andrandomized. For intravenous administration, a freshly prepared solutionof a compound of the present disclosure is administered at a dose levelof 1 mg/kg via tail vein at a slow and steady rate. The dosing volumefor intravenous administration is 5 mL/kg. Freshly prepared suspensionof a compound of the present disclosure is administered at an oral doseof 10 mg/kg, by stomach intubation using a 16 gauge oral feeding needle.The dosing volume for oral dose group is 10 mL/kg.

Blood samples: Blood samples (0.06 mL) are collected from saphenous veinof each mouse at regular intervals. During each sampling point, bloodsamples are collected in labeled microtubes containing K2EDTA as ananticoagulant. Samples are centrifuged at 4000 rpm for 10 min at 4±2° C.(Centrifuge Model: Kubota 3500). The recovered quantity of plasma fromeach sample is transferred to labeled micro-tubes. The plasma samplesare stored at −70° C. until bioanalysis.

Bioanalysis of samples: Bioanalytical method for the determination of acompound of the present disclosure in mouse plasma is developed usingLC-MS/MS equipment. The method is partially validated prior to sampleanalysis.

Pharmacokinetic analysis: The pharmacokinetic parameters of a compoundof the present disclosure such as T_(max), C_(max), AUC, CL, V_(d),T_(1/2), and bioavailability in mouse plasma are determined from theconcentration-time data using non-compartmental analysis (WinNonlinEnterprise version 5.2, Pharsight Corporation, USA).

Serum Creatinine and White Blood Cell Count Analyses

Blood is collected from vehicle and compound of Formula (I′) treatedmice into appropriate tubes and analyzed at the clinical laboratory atthe Boston Children's Hospital.

Statistical Analyses

Statistical analyses were performed using an unpaired two tailedStudent's t-test. A p value of less than 0.05 was consideredsignificant.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, wherein: R₁ is phenyl or heteroarylcomprising one or two 5- or 6-membered rings and 1-4 heteroatomsselected from N, O, and S, wherein the phenyl or heteroaryl isoptionally substituted with one or more R₈; each R₈ is independentlyhalogen, (C₁-C₃) alkyl, (C₁-C₃) haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃)haloalkoxy, OH, NH₂, NH(C₁-C₃) alkyl, or N((C₁-C₃) alkyl)₂; R₂ is H or(C₁-C₃) alkyl; R₃ is

R₆ is (C₂-C₄) alkenyl optionally substituted with one or more R₉; eachR₉ is independently NH₂, NH(C₁-C₃) alkyl, N((C₁-C₃) alkyl)₂, orheterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatomsselected from N, O, and S, wherein the heterocyclyl is optionallysubstituted with one or more substituents independently selected fromhalogen, OH, and C(O)(C₁-C₃) alkyl; R₇ is H or (C₁-C₃) alkyl; R₄ is

R₁₀ is (C₁-C₃) alkyl optionally substituted with C(O)NH—(C₁-C₃) alkyl,C(O)N((C₁-C₃) alkyl)₂, or a heterocyclyl comprising a 5- or 6-memberedring and 1-3 heteroatoms selected from N, O, and S, or R₁₀ isheterocyclyl comprising a 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S optionally substituted with one or more(C₁-C₃) alkyl; each R₁₁ is independently (C₁-C₃) alkyl, (C₁-C₃)haloalkyl, (C₁-C₃) alkoxy, (C₁-C₃) haloalkoxy, or halogen; n is 0, 1, or2; and R₅ is H or (C₁-C₃) alkyl; provided that when R₂, R₅ and R₇ areeach H, R₆ is ethenyl, and R₄ is

then R₁ is not unsubstituted phenyl.
 2. The compound of claim 1, whereinR₁ is phenyl optionally substituted with one or more R₈.
 3. The compoundof claim 1, wherein R₁ is pyridinyl optionally substituted with one ormore R₈.
 4. The compound of claim 1, wherein R₁ is benzothiophenyloptionally substituted with one or more R₈.
 5. The compound of claim 1,wherein R₂ is H.
 6. The compound of claim 1, wherein R₂ is methyl. 7.The compound of claim 1, wherein R₆ is ethenyl.
 8. The compound of claim1, wherein R₆ is ethenyl substituted with one or more R₉.
 9. Thecompound of claim 1, wherein R₇ is H.
 10. The compound of claim 1,wherein R₅ is H.
 11. The compound of claim 1, wherein R₄ is


12. The compound of claim 1, wherein R₄ is


13. The compound of claim 1, wherein R₈ is halogen.
 14. The compound ofclaim 13, wherein R₈ is F.
 15. The compound of claim 1, wherein R₁₀ isunsubstituted methyl.
 16. The compound of claim 1, wherein R₁₀ is methylor ethyl substituted with morpholino.
 17. The compound of claim 1,wherein R₁₀ is methyl or ethyl substituted with C(O)NH—(C₁-C₃) alkyl.18. The compound of claim 1, wherein R₁₀ is heterocyclyl comprising a 5-or 6-membered ring and 1-3 heteroatoms selected from N, O, and Soptionally substituted with one or more (C₁-C₃) alkyl.
 19. The compoundof claim 1, having structural Formula (Ia) or (Ib):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.
 20. The compound of claim 1,selected from the group consisting of: benzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;3-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;3-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;benzo[b]thiophen-2-ylmethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;benzo[b]thiophen-2-ylmethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-chlorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;4-chlorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;(5-fluoropyridin-2-yl)methyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;(5-fluoropyridin-2-yl)methyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;(6-fluoropyridin-3-yl)methyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;(6-fluoropyridin-3-yl)methyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;(R)-1-phenylethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;(R)-1-phenylethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;(S)-1-phenylethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;(S)-1-phenylethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;benzo[b]thiophen-3-ylmethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)carbamate;benzo[b]thiophen-3-ylmethyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(E)-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(3-(4-(piperidin-1-yl)but-2-enamido)phenyl)carbamate;4-fluorobenzyl(E)-(3-(4-(4-hydroxypiperidin-1-yl)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(E)-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)(3-(4-morpholinobut-2-enamido)phenyl)carbamate;4-fluorobenzyl(E)-(3-(4-(azepan-1-yl)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(E)-(3-(4-(dimethylamino)but-2-enamido)phenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;2,4-difluorobenzyl(3-acrylamidophenyl)(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;4-fluorobenzyl(3-acrylamidophenyl)(2-((1-(2-(methylamino)-2-oxoethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate;and 4-fluorobenzyl(3-acrylamidophenyl)(2-((1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)carbamate,or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.
 21. A pharmaceutical compositioncomprising a compound of claim 1, and a pharmaceutically acceptablecarrier.
 22. A method of inhibiting a kinase or epidermal growth factorreceptor (EGFR), comprising administering to a subject in need thereofan effective amount of a compound of claim
 1. 23. (canceled)
 24. Amethod of treating or preventing a disease in which EGFR plays a role,comprising administering to a subject in need thereof an effectiveamount of a compound of claim
 1. 25.-27. (canceled)